EP1773829B1 - Amino-tropane derivatives, preparation thereof and therapeutic use thereof - Google Patents

Amino-tropane derivatives, preparation thereof and therapeutic use thereof Download PDF

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EP1773829B1
EP1773829B1 EP05790816A EP05790816A EP1773829B1 EP 1773829 B1 EP1773829 B1 EP 1773829B1 EP 05790816 A EP05790816 A EP 05790816A EP 05790816 A EP05790816 A EP 05790816A EP 1773829 B1 EP1773829 B1 EP 1773829B1
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cyclohexyl
group
oct
azabicyclo
diethylurea
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German (de)
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EP1773829A1 (en
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Alain Braun
Bruno Cornet
Gilles Courtemanche
Olivier Crespin
Cécile PASCAL
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Sanofi Aventis France
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Sanofi Aventis France
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Priority to PL05790816T priority Critical patent/PL1773829T3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to melanocortin receptor agonist compounds, their preparation and their therapeutic application.
  • MC-Rs Melanocortin receptors
  • MC-Rs belong to the G-protein coupled receptor super-family with seven transmembrane domains. Their transduction pathway involves the production of cAMP ( Cone, RD, Recent Prog. Horm. Res., 1996, 51, 287 ).
  • Five subtypes of MC-Rs are currently described, MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, and are expressed in different tissues such as the brain (MC3, 4, 5-R) , the exocrine glands (MC5-R), the adrenal glands (MC2-R) and the skin (MC1-R) for the main ones.
  • the natural ligands of the MC-Rs are, for the agonists, the ACTH, the ⁇ , ⁇ and ⁇ -MSH, and for the antagonists, the agouti protein and the agoutirelated protein. None of the natural ligands is highly selective for any of the subtypes, except for ⁇ -MSH, which has some selectivity for MC3-R.
  • the melanocortin system is involved in many physiological processes, including pigmentation, inflammation, eating and sexual behavior (including erectile function), energy balance (body weight regulation and lipid storage), exocrine function, protection and neuronal regeneration, immunomodulation, analgesia, etc.
  • MC4-R is involved in sexual behavior ( Van der Ploeg, LH, Proc. Natl. Acad. Sci. USA, 2002, 99, 11381 ; Martin, WJ, Eur. J. Pharmacol., 2002, 454, 71 ). It has also been demonstrated, through mouse models specifically lacking in some MC-Rs (knockout mice), that central MC-Rs (MC3 and 4-R) were involved in eating behavior, obesity, metabolism and energy balance ( Huszar, D., Cell, 1997, 88 (1), 131 ; Chen, AS, Nat. Genet., 2000, 26 (1), 97 ; Butler, AA, Trends Genet., 2001, 17, S50-S54 ).
  • MC4-R knockout mice are hyperphagic and obese.
  • MC3 and / or 4R antagonists favor food intake, whereas stimulation of MC4-R by an endogenous agonist, such as ⁇ -MSH, produces a satiety signal.
  • the compounds of formula (I) comprise at least one asymmetric carbon atom. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
  • the compounds of formula (I) according to the invention may also exist in the form of mixtures of conformers, which are also part of the invention. They can additionally exist in the form of cis or trans isomers, or in the form of endo or exo isomers. These isomers and their mixture are part of the invention.
  • the tropane nucleus of the compounds of formula (I) according to the invention advantageously has an endo configuration, as represented below:
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
  • R a , R a ' , R 2 , R 3 , R 4 and R 5 are as defined above and R 1 represents a alkyl, cycloalkyl, heterocycloalkyl or phenyl group.
  • R 1 represents a cycloalkyl group, such as a cyclohexyl group.
  • R 2 represents a group -CO-NR 16 R 17 , where R 16 and R 17 represent alkyl or alkoxy groups.
  • R 2 advantageously represents a -CO-NR 16 R 17 group , or R 16 and R 17 represent alkyl groups.
  • R a , R a ' , R 1 , R 2 , R 4 and R 5 are as defined above and R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms.
  • R 3 represents a single group, preferably a chlorine atom.
  • R 6 represents a -NH 2 or phenyl group
  • R 7 represents a hydrogen atom or a hydroxyl group
  • R 10 represents a hydrogen atom or an aryl, alkylaryl or form, with the nitrogen atom to which it is attached and a a carbon atom at any position in the ring structure of formula (a-1), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members.
  • R 10 represents a hydrogen atom in the group of formula (b-1) and, in the group of formula (a-1), a hydrogen atom or a phenyl, benzyl or form group, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of formula (a-1), but not adjacent to said nitrogen atom, a bridge comprising 4 links.
  • R 6 represents a group -NH 2 or phenyl
  • R 7 represents an atom of hydrogen or a hydroxyl group
  • R 10 represents a hydrogen atom or an aryl, alkylaryl or form group, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of the formula (a-5), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members.
  • R 10 represents a hydrogen atom in the group of formula (b-2) and, in the group of formula (a-5), a hydrogen atom or a phenyl or benzyl group or forms, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of formula (a-5), but not adjacent to said nitrogen atom, a bridge comprising 4 links.
  • R a , R a ' , R 1 , R 2 , R 3 and R 4 are as defined above and R 5 represents a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms.
  • R 5 preferably represents a hydrogen atom.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above and R a and R a ' represent hydrogen atoms or alkyl groups having 1 to 4 carbon atoms.
  • R a and R a ' represent, independently of one another, hydrogen atoms or methyl groups.
  • R 6 represents a hydrogen atom or a group -NR 8 R 9 or aryl, in which R 8 and R 9 represent a hydrogen atom or an alkyl group.
  • R 6 representing a hydrogen atom or a group -NH 2 or phenyl.
  • R 7 represents a hydrogen or halogen atom or an alkyl or hydroxyl group (corresponding to a group -OR, where R represents a hydrogen atom) or alkoxy (corresponding to a group -OR, where R represents an alkyl group).
  • R 7 advantageously represents a hydrogen atom or a hydroxyl group.
  • R 8 and R 9 represent a hydrogen atom or an alkyl group.
  • R 10 represents a hydrogen atom or an aryl group (such as a phenyl group) or alkylaryl (such as a benzyl group), or R 10 forms, with the nitrogen atom that carries it and a carbon atom located at any position of the ring structure to which it is attached, but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members.
  • R and R ' defined above, there may be mentioned those in which R and R' represent a hydrogen atom or an alkyl group.
  • a protective group is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis.
  • Examples of protecting groups as well as methods of protection and deprotection are given in "Protective Groups in Organic Synthesis," Green W. et al., 1999, 3rd Edition (John Wiley & Sons, Inc., New York) ).
  • leaving group (Lg) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of starting groups as well as references for their preparation are given in March's Advanced Organic Chemistry, J. March et al., 5th Edition, 2001, EMInter Ed .
  • Boc group means a t-butoxycarbonyl group, Bn a benzyl group, CBz a benzyloxycarbonyl group, Fmoc a 9-fluorenylmethyl-carbamate group, and by h the hours
  • the compounds of general formula (I) can be prepared according to the process shown in Scheme 1.
  • the compounds of formula (IV) may be prepared by coupling between the intermediates of formula (II) and an amino acid of formula (III), the amine function of which is protected by a protective group Pg (for example a Boc group) , CBz or Fmoc), under conventional peptide coupling conditions, for example using as the coupling agent dicyclocarbodiimide, hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in presence or absence of hydroxybenzo-triazole, and as base triethylamine or diisopropylethylamine in a solvent such as dioxane, dichloromethane or acetonitrile.
  • a protective group Pg for example a Boc group
  • amino acids of general formula (III) are commercially available or can be prepared by methods described in the literature ( Williams, RM, Synthesis of Optically Active ⁇ -Aminoacids, Pergamon Press, Oxford, 1989 ).
  • the compounds of formula (V) are obtained by deprotection of the amine function of the compounds of formula (IV), by methods chosen from those known to those skilled in the art. They include inter alia the use of trifluoroacetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection with a Boc group, hydrogenation with the appropriate metal in methanol or ethanol in the case of a CBz, and piperidine for a Fmoc group, at temperatures ranging from -10 ° C to 100 ° C.
  • the compounds of formula (I) are obtained by reductive amination, carried out by bringing the compounds of formula (V) in the presence of a derivative of the R 4 group of the oxo (aldehyde or ketone) type, using a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or absence of a Bronsted acid (such as hydrochloric acid) or Lewis acid (such as titanium tetraisopropoxide) in a solvent such as dichloroethane, dichloromethane, acetic acid or methanol at temperatures between -10 ° C and 30 ° C.
  • a Bronsted acid such as hydrochloric acid
  • Lewis acid such as titanium tetraisopropoxide
  • the aldehydes derived from the R 4 group when they are not commercial, are prepared from the corresponding acids by methods known to those skilled in the art, for example by conversion into Weinreb amide under peptide coupling conditions. and then reducing it with a hydride such as lithium aluminum hydride.
  • R 4 ketone or aldehyde group derivatives may be commercial or obtained by methods known to those skilled in the art, for example by acylation of the amine or free hydroxyl function of the ketone derivative.
  • the compounds of formula (VIII) can be obtained by reductive amination, as described above, carried out from the amino acids of formula (VII).
  • R 5 represents an alkyl group
  • the amino acids of formula (VII) can be prepared by alkylation of the protected commercial amino acid on the amine function, according to the alkylation methods known to those skilled in the art.
  • the compounds of formula (IX) may be synthesized by saponification of the esters of formula (VIII), for example in the presence of sodium hydroxide or of lithium hydroxide in a solvent such as methanol, tetrahydrofuran or water, or a mixture of these solvents.
  • the compounds of general formula (VI) may be prepared by peptide coupling between the intermediates of formula (II) and the amino acid of formula (IX), under peptide coupling conditions as described in scheme 1.
  • the compounds of formula (II) may be prepared from the compound of formula (X) (where Pg is an amine protecting group, as defined in scheme 1), after deprotection of the amine function by methods selected from those known to those skilled in the art, as described above.
  • the compound of formula (X) is prepared according to the methods described in the literature or known to those skilled in the art, adapted according to the nature of the groups R 1 and R 2 .
  • Diagrams 5 to 9 below show examples of the preparation of compounds of formula (X) according to different types of group R 2 .
  • R 2 represents a group -CO-R 15 , where R 15 is as defined above
  • the preparation of the corresponding compound (Xa) can be carried out according to scheme 5.
  • the compounds of formula (XI) can be obtained by reductive amination, under the conditions described above, of nortropanone. whose amine function is protected (eg commercial Boc-nortropanone).
  • the compounds of formula (Xa) are then obtained by reacting the compounds of formula (XI) with an acid chloride of formula R 15 COCl, in the presence of an organic base such as triethylamine or pyridine, in a solvent such as than dichloromethane or tetrahydrofuran.
  • Scheme 6 shows a route of preparation of the compounds of formula (Xb) and (Xc), which respectively correspond to the compounds of formula (X) in which R 2 represents a group -CO-NR 16 R 17 and -CO-NR 15 -NR 16 R 17 , where R 15 , R 16 and R 17 are as defined above.
  • the compounds of formula (XII) may be prepared from compounds of formula (XI) by reaction with phosgene, triphosgene or trichloromethyl chloroformate in dichloromethane or toluene in the presence of triethylamine or pyridine and an amine at temperatures ranging from -10 ° C to 80 ° C.
  • the reaction of the compounds of formula (XII) with an amine of formula HN (R 16 ) (R 17 ) or a hydrazine of formula HN (R 15 ) (NR 16 R 17 ) results respectively in the compounds of formulas (Xb) and ( xc).
  • the compounds of formula (XIII) can be obtained by reductive amination carried out on the compounds of formula (XI) in the presence of an aldehyde of formula Q-CO- (CH 2 ) x-2 -CHO, where Q is -O-alkyl or -N (O-alkyl) (alkyl), using a reductant as described above in connection with Scheme 1.
  • the compounds of formula (Xd) may then be prepared by reductive amination carried out in the presence of an amine of formula R 17 R 16 NH, using a reducing agent as described above.
  • the compounds of formulas ( Xe) in which R 2 represents a - (CH 2 ) x -aryl group can then be obtained by reductive amination from the compounds of formula (XI) ii, carried out in the presence of an oxo-type derivative of R 1 group.
  • Scheme 9 details an alternative for the synthesis of compounds of formula (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group, where x is 2 or 3.
  • the compounds of formula (XIII), in which Q represents a -O-alkyl group can be reduced to the corresponding alcohols by using a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran, at temperatures ranging from -60 ° C to 20 ° C.
  • a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran
  • the hydroxyl group of the compounds of formula (XV) is then converted into a leaving group (Lg), such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of sodium chloride.
  • a leaving group such as chloride or mesylate
  • methanesulfonyl in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C to room temperature, to yield compounds of formula (XVI).
  • the compounds of formula (Xe) are then synthesized by a nucleophilic substitution reaction between the compounds of formula (XVI) and the anion of a heteroaryl ("Het" group).
  • the compounds of formula (XX) are prepared under standard conditions, such as by conversion of the hydroxyl group of compounds of formula (XXI) into a leaving group, such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of methanesulfonyl chloride in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C to room temperature.
  • the compounds of formula (XXI) are synthesized according to the alkylation methods known to those skilled in the art of commercial 1,2,3,4-tetrahydroisoquinoline.
  • the compounds of formula (XVIII) can be obtained by reductive amination between the compound of formula (XVII) and the commercial compounds of formula (V) under conditions as described in Scheme 1.
  • R 8 is different from a hydrogen atom
  • functionalization of the compounds of formula (If) is carried out, for example alkylation in the presence of a base such as sodium hydride and a group R derivative. 8 having a leaving group Lg, which results in the compounds of formula (lg).
  • the invention also relates to the compounds of formulas (II), (IV), (V), (VI), (VIII), (IX), (X), (XVIII) and (XIX): these compounds are useful as synthesis intermediates for the compounds of formula (I).
  • the crude product obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 10%. 7.7 g of the endo tert-butyl 3- (cyclohexylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate compound and 1.2 g of the exo tert-butyl 3- (cyclohexylamino) -8-azabicyclo compound are obtained. [3.2.1] octane-8-carboxylate. The rest of the synthesis concerns the endo compound.
  • N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ' , N' -diethylurea are solubilized in 4 parts by volume.
  • mL of N 2 dichloromethane in the presence of 0.17 g of N- BOC-piperidone and 0.23 g of sodium triacetoxyborohydride and stirred for 16 h at room temperature. After evaporation and hydrolysis, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted.
  • tert -butyl 3 0.21 g of tert -butyl 3 is placed - ⁇ [(1 R) -1- (4-chlorobenzyl) -2- (3- ⁇ cyclohexyl [(diethylamino) carbonyl] amino ⁇ -8-azabicyclo [3.2.1 ] oct-8-yl) -2-oxoethyl] amino ⁇ -8-azabicyclo [3.2.1] octane-8-carboxylate in 1.53 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred overnight at room temperature. Triturated, rinsed with diethyl ether and the precipitate obtained is filtered off.
  • reaction medium is stirred for 16 hours at room temperature. After hydrolysis with an aqueous solution of 0.5N hydrochloric acid, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is dried over MgSO 4 and concentrated to dryness. Is obtained 0.9 g of tert -butyl (2 S, 4 R) -4-hydroxy-2 - ⁇ [methoxy (methyl) amino] carbonyl ⁇ pyrrolidine-1-carboxylate which was used as such subsequently.
  • step 6.5 0.088 g of hydroxybenzotriazole, 0.125 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.17 ml of diisopropylethylamine.
  • the mixture is stirred 16h at room temperature. After evaporation to dryness, the residue is hydrolysed and extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 3%.
  • the compounds according to the invention have been the subject of pharmacological tests for determining their agonist effect of melanocortin receptors, in particular their agonist effect of the MC3 and / or MC4 receptor.
  • This affinity test is carried out by measuring the binding of [ 125 I] - [Nle 4 -D-Phe 7 ] - ⁇ -MSH to cell membranes: the displacement of this radioligand is used to identify inhibitors of specific binding to recombinant melanocortin receptors.
  • membranes prepared from CHO-K1 cells expressing the high density human MC4 receptor (Euroscreen) or purchased membranes (Perkin Elmer Life Sciences, Receptor Biology) of HEK-293 cells expressing hMC3 receptors are used.
  • the CHO-K1 cells transfected with the hMC4 receptor gene (Euroscreen) are seeded in the DMEM / Nutrient Mix F12 culture medium containing 10% calf serum (Biowhittaker), 1% sodium pyruvate, 1% L-glutamine, 1 % non-essential amino acids, 0.4 mg / ml geneticin (G418) and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum.
  • the cells are scraped at 80% confluency and the cell pellets are frozen at -80 ° C.
  • a tube of cells (approximately 70 x 10 6 cells) is thawed on ice and resuspended in 10 ml of binding buffer [25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 100 mM NaCl, 1 mM 1 , 10-phenanthroline and 1 tablet of Complete TR (Roche protease inhibitor) in 50 ml buffer] by 20 sec. The suspension is centrifuged for 20 minutes at 19500 rpm at 4 ° C. The supernatant is discarded and the pellet is resuspended in 5 ml of binding buffer.
  • binding buffer [25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 100 mM NaCl, 1 mM 1 , 10-phenanthroline and 1 tablet of Complete TR (Roche protease inhibitor) in 50 ml buffer] by 20 sec.
  • the products to be tested (diluted in 10% DMSO), in an amount of 10 ⁇ l at a concentration of 10 times the final concentration, are distributed in a white-colored 96-well plate (CORNING 3604 Polystyrene Non-Binding Surface).
  • the nonspecific binding is defined by NDP- ⁇ MSH at 10 -7 M.
  • the total binding is measured by the number of counts per minute in the presence of the radioligand alone.
  • the distribution of the membrane-bead suspension (50 ⁇ l / well) is followed by the distribution of the solution of [ 125 I] - [Nle 4 , D-Phe 7 ] - ⁇ -MSH, 40 ⁇ l / well (100 ⁇ M final concentration), for a final volume of 100 ⁇ l / well. After 6 pm incubation at room temperature, counting is done in a Microbeta TriLux scintillation counter.
  • the IC 50 value of the compounds corresponds to the concentration which displaces the specific binding of the radioligand by
  • the compounds according to the invention have an affinity for the MC3 and / or MC4 receptors.
  • Their IC 50 towards the MC3 and MC4 receptors are less than 10 ⁇ M, mostly between 1 nM and 1 ⁇ M.
  • Compound No. 3 of the table has an IC 50 of 280 nM towards the MC4 receptor.
  • a functional test is used to discriminate the agonist activity of the antagonist activity.
  • the adenosine-cyclic mono-phosphate (cAMP) formation generated by the activation of the MC3 receptor or the MC4 receptor is measured.
  • the CHO-K1 cells expressing the human MC4 receptor at a moderate density (Euroscreen), are seeded in the DMEM / Nutrient Mix F12 culture medium (Gibco / BRI) containing 10% calf serum, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-essential amino acids, 200 mg / l hygromycin B and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum (Biowhittaker) and hygromycin B (Sigma) .
  • Gibco / BRI containing 10% calf serum, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-essential amino acids, 200 mg / l hygromycin B and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum (Biowhittaker) and hygromycin B (Sigma) .
  • the CHO cells (dhfr-) expressing the human MC3 receptor are seeded in the Eagle (Sigma) MEM culture medium containing 10% dialyzed calf serum, 1% L-glutamine, 1% sodium pyruvate, 20 mg / 500 ml. -proline, 0.3 mg / ml Geneticin and 0.5% PenStrep, these products being supplied by Gibco / BRI, except dialyzed calf serum (Cambrex) and L-proline (Sigma).
  • the intrinsic activity of the compounds is calculated by comparing cAMP stimulation by these compounds to stimulation induced by 30 nM NDP ⁇ MSH (100% maximum). The EC 50 value of the compounds corresponds to the concentration which produces 50% of the maximal stimulation obtained with this compound.
  • the compounds according to the invention are agonists of the MC3 and / or MC4 receptors. They have EC 50 towards MC3 and MC4 receptors less than 10 ⁇ M, mostly between 1 nM and 1 ⁇ M.
  • compound No. 3 of the table shows an EC 50 of 330 nM towards the MC3 receptor, and 28 nM towards the MC4 receptor.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of compound of formula (I).
  • these drugs find their therapeutic use, in the pathologies in which the melanocortin receptors, in particular the MC3 and / or MC4 receptors, are involved: these include the treatment and prevention of obesity, diabetes and sexual dysfunction that can affect both sexes, such as erectile dysfunction, cardiovascular diseases such as myocardial infarction or hypertension, as well as anti-inflammatory or alcohol dependence treatment.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention:
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a salt pharmaceutically acceptable, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a preferred form of administration is the oral route.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

Abstract

The invention concerns amino-tropane derivatives of general formula (I), wherein: Ra R a' et R5 represent hydrogen atoms or alkyl groups; R1 represents a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl or aryl group; R2 represents a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, wherein Y represents a hydrogen atom or a hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl group or NR11R12; R3 represents 1 to 3 groups selected among halogen atoms and alkyl, cycloalkyl OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR groups; R4 is selected among a group of formula (a), (b), (c) or (d): or a group of formula -A-R18, -A-CH=N-R19, -A-N(R20)-A'-R19, -A-CO-N(R2O)-A'-R19, -A-CH(NH2)-R19, -A-N(R20)-COO-A' or -(CH2)r-heteroaryl. The invention also concerns a method for preparing said derivatives and the therapeutic use thereof.

Description

La présente invention se rapporte à des composés agonistes des récepteurs aux mélanocortines, à leur préparation et à leur application en thérapeutique.The present invention relates to melanocortin receptor agonist compounds, their preparation and their therapeutic application.

Les récepteurs aux mélanocortines (MC-Rs) appartiennent à la super-famille des récepteurs couplés aux protéines G présentant sept domaines transmembranaires. Leur voie de transduction passe par la production d'AMPc ( Cone, R. D., Recent Prog. Horm. Res., 1996, 51, 287 ). Cinq sous types de MC-Rs sont actuellement décrits, MC1-R, MC2-R, MC3-R, MC4-R et MC5-R, et sont exprimés dans différents tissus tels que le cerveau (MC3, 4, 5-R), les glandes exocrines (MC5-R), les surrénales (MC2-R) et la peau (MC1-R) pour les principaux. Les ligands naturels des MC-Rs sont, pour les agonistes, l'ACTH, l'α, β et γ-MSH, et pour les antagonistes, l'agouti protéine et l'agoutirelated protéine. Aucun des ligands naturels n'est très sélectif pour l'un des sous-types, à l'exception du γ-MSH, qui possède une certaine sélectivité pour le MC3-R.Melanocortin receptors (MC-Rs) belong to the G-protein coupled receptor super-family with seven transmembrane domains. Their transduction pathway involves the production of cAMP ( Cone, RD, Recent Prog. Horm. Res., 1996, 51, 287 ). Five subtypes of MC-Rs are currently described, MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, and are expressed in different tissues such as the brain (MC3, 4, 5-R) , the exocrine glands (MC5-R), the adrenal glands (MC2-R) and the skin (MC1-R) for the main ones. The natural ligands of the MC-Rs are, for the agonists, the ACTH, the α, β and γ-MSH, and for the antagonists, the agouti protein and the agoutirelated protein. None of the natural ligands is highly selective for any of the subtypes, except for γ-MSH, which has some selectivity for MC3-R.

Le système mélanocortine est impliqué dans de nombreux processus physiologiques, incluant la pigmentation, l'inflammation, le comportement alimentaire et sexuel (notamment la fonction érectile), la balance énergétique (régulation du poids corporel et stockage lipidique), les fonctions exocrines, la protection et régénération neuronale, l'immunomodulation, l'analgésie, etc ...The melanocortin system is involved in many physiological processes, including pigmentation, inflammation, eating and sexual behavior (including erectile function), energy balance (body weight regulation and lipid storage), exocrine function, protection and neuronal regeneration, immunomodulation, analgesia, etc.

Notamment, il a été démontré que le MC4-R est impliqué dans le comportement sexuel ( Van der Ploeg, L. H., Proc. Natl. Acad. Sci. USA, 2002, 99, 11381 ; Martin, W. J., Eur. J. Pharmacol., 2002, 454, 71 ). Il a également été démontré, par l'intermédiaire de modèles de souris spécifiquement dépourvues en certains MC-Rs (souris knockout), que les MC-Rs centraux (MC3 et 4-R) étaient impliqués dans le comportement alimentaire, l'obésité, le métabolisme et la balance énergétique ( Huszar, D., Cell, 1997, 88(1), 131 ; Chen, A. S., Nat. Genet., 2000, 26(1), 97 ; Butler, A.A., Trends Genet., 2001, 17, S50-S54 ). Ainsi, les souris knockout MC4-R sont hyperphagiques et obèses. Parallèlement, les antagonistes aux MC3 et/ou 4R favorisent la prise de nourriture, tandis que la stimulation des MC4-R par un agoniste endogène, tel que l'α-MSH, produit un signal de satiété.In particular, it has been shown that MC4-R is involved in sexual behavior ( Van der Ploeg, LH, Proc. Natl. Acad. Sci. USA, 2002, 99, 11381 ; Martin, WJ, Eur. J. Pharmacol., 2002, 454, 71 ). It has also been demonstrated, through mouse models specifically lacking in some MC-Rs (knockout mice), that central MC-Rs (MC3 and 4-R) were involved in eating behavior, obesity, metabolism and energy balance ( Huszar, D., Cell, 1997, 88 (1), 131 ; Chen, AS, Nat. Genet., 2000, 26 (1), 97 ; Butler, AA, Trends Genet., 2001, 17, S50-S54 ). Thus, MC4-R knockout mice are hyperphagic and obese. At the same time, MC3 and / or 4R antagonists favor food intake, whereas stimulation of MC4-R by an endogenous agonist, such as α-MSH, produces a satiety signal.

Ces observations laissent penser que la stimulation du MC3-R et/ou du MC4-R central, en réduisant la prise de nourriture et le poids corporel, est une approche prometteuse pour traiter l'obésité, risque aggravant de nombreuses autres pathologies (hypertension, diabète, ...). Ainsi, les recherches ont permis d'identifier dans un premier temps des peptides, pseudo-peptides ou peptides cycliques, capables d'interagir avec les MC-Rs et de moduler ainsi la prise de nourriture.These observations suggest that stimulation of MC3-R and / or MC4-R central, reducing food intake and body weight, is a promising approach to treat obesity, a risk aggravating many other pathologies (hypertension, diabetes, ...). Thus, the research made it possible to first identify peptides, pseudo-peptides or cyclic peptides capable of interacting with MC-Rs and thus modulating food intake.

Afin de maintenir sur le long terme une perte de poids efficace et limiter ainsi les, co-morbidités, un traitement quotidien à long terme doit être envisagé. Ceci implique qu'un médicament, pour cette indication thérapeutique, doit pouvoir être administré par une voie simple pour le patient. La voie orale doit donc être privilégiée. Or, les composés peptidiques ne sont généralement pas les plus appropriés pour répondre à cette obligation. C'est pourquoi il est important de développer des petites molécules non peptidiques.In order to maintain effective weight loss over the long term and thus limit co-morbidities, a long-term daily treatment should be considered. This implies that a drug for this therapeutic indication must be able to be administered by a simple route for the patient. The oral route must therefore be preferred. However, peptide compounds are generally not the most appropriate to meet this obligation. This is why it is important to develop small nonpeptide molecules.

Dans cette optique, les demandes internationales PCT publiées sous les numéros WO 02/059095 , WO 02/059108 , WO 03/009850 et WO 03/061660 décrivent des dérivés de type pipérazine. D'autres demandes décrivent des dérivés de type pipéridine, telles que les WO 03/092690 et WO 03/093234 . Les demandes WO 99/64002 et WO 01/70337 décrivent des dérivés de type spiro-pipéridine. La demande WO 01/91752 décrit des dérivés comportant un motif pipéridine fusionné avec un noyau pyrazolyle. La demande WO 02/059107 décrit des dérivés de type pipéridine et pipérazine substitués par une structure bicyclique. Les demandes WO 02/059117 , WO 02/068388 et WO 03/009847 décrivent des dérivés de type pipéridine et/ou pipérazine substitués par un noyau phényle. Quant à la demande WO 03/094918 , elle décrit des dérivés de type pipérazine substitués par un noyau phényle ou pyridinyle. On peut également citer les demandes WO 00/74679 , WO 01/70708 , WO 02/15909 , WO 02/079146 , WO 03/007949 et WO 04/024720 , qui décrivent des dérivés de type pipéridine substituée, ou encore la demande WO 04/037797 ; les composés décrits dans ces demandes de brevets comportent toujours une fonction amide, mimant les structures peptidiques antérieurement connues.With this in mind, the PCT international applications published under the WO 02/059095 , WO 02/059108 , WO 03/009850 and WO 03/061660 describe piperazine derivatives. Other applications describe piperidine derivatives, such as WO 03/092690 and WO 03/093234 . The requests WO 99/64002 and WO 01/70337 describe spiro-piperidine derivatives. Requirement WO 01/91752 discloses derivatives having a piperidine unit fused with a pyrazolyl ring. Requirement WO 02/059107 describes piperidine and piperazine derivatives substituted with a bicyclic structure. The requests WO 02/059117 , WO 02/068388 and WO 03/009847 describe piperidine and / or piperazine derivatives substituted with a phenyl ring. As for the demand WO 03/094918 it describes piperazine derivatives substituted with a phenyl or pyridinyl ring. We can also mention the requests WO 00/74679 , WO 01/70708 , WO 02/15909 , WO 02/079146 , WO 03/007949 and WO 04/024720 , which describe substituted piperidine derivatives, or the application WO 04/037797 ; the compounds described in these patent applications always include an amide function, mimicking the previously known peptide structures.

Face au besoin constant d'améliorer les thérapies existantes pour les pathologies évoquées précédemment, les Inventeurs se sont donnés pour but de pourvoir à de nouveaux composés agonistes des récepteurs aux mélanocortines. La présente invention a pour objet des composés répondant à la formule (I)

Figure imgb0001
dans laquelle :

  • Ra et Ra ,, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle ou cycloalkyle,
  • R1 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle ou aryle,
  • R2 représente un groupe de formule -(CH2)x(CO)y-Y ou -(CO)y-(CH2)x-Y, dans laquelle :
    • x=0, 1, 2, 3 ou 4,
    • y= 0 ou 1,
    • Y représente un atome d'hydrogène ou un groupe hydroxyle, alkyle, cycloalkyle, alcoxy, aryle, hétéroaryle ou -NR11R12, Y étant différent d'un atome d'hydrogène lorsque x=y=0,
    • R11 et R12, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle, alcoxy ou -NR13R14, ou bien R11 et R12 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono-ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy. A titre d'exemples de telles structures cycliques, on peut citer les groupes pyrrolidinyle, morpholinyle, pyrrolinyle, isoindolinyle, etc ...,
    • R13 et R14, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien R13 et R14 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique telle que définie ci-dessus,
  • R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, situés en des positions quelconques du noyau auquel ils sont rattachés et choisis parmi les atomes d'halogène et les groupes alkyles, cycloalkyles, -OR, -NRR', -CO-NRR', -NR-COR', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR, où R et R' sont tels que définis ci-dessous,
  • R5 représente un atome d'hydrogène ou un groupe alkyle ou cycloalkyle,
  • R4 est choisi parmi :
    1. (1) un groupe de formule (a), (b) ou (c) éventuellement substitué par un groupe oxo:
      Figure imgb0002
       dans lesquelles chacun des cycles de formules (a), (b) et (c) peut être substitué, en des positions quelconques, par 1 à 4 groupes R7, identiques ou différents les uns des autres, et dans lesquelles :
      • a = 0, 1, 2 ou 3,
      • p = 0, 1, 2 ou 3,
      • m = 0, 1 ou 2,
      • X représente un atome d'oxygène ou de soufre ou un chaînon -C(R6)(R7)- ou -N(R10)-,
    R6 est choisi parmi :
    • un atome d'hydrogène, un atome d'halogène
    • un groupe -(CH2)x OR8, -(CH2)xCOOR8, -(CH2)x NR8R9, -(CH2)x-CO-NR8R9 ou -(CH2)x-NR8-COR9, dans lesquels x = 0, 1, 2, 3 ou 4 et R8 et R9 sont tels que définis ci-dessous,
    • un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle ou -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9,
    • un groupe cycloalkyle ou hétérocycloalkyle fusionné ou non situé en position spiro sur le cycle de formule (a) auquel il est rattaché,
    • un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle,
    R7 est choisi parmi les atomes d'hydrogène et d'halogène et les groupes alkyles, cycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -OR, -O-aryles, -O-hétéroaryles, -O-alkylaryles, -O-alkylhétéroaryles, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR, où R et R' sont tels que définis ci-dessous,
    • R 8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles -SO2-cycloalkyles, -SO2-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)x-OR, où x = 0, 1, 2, 3 ou 4 et R et R' sont tels que définis ci-dessous, les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles et hétéroaryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les les groupes R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR'
    ou bien R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle ;
    R10 est choisi parmi :
    • un atome d'hydrogène,
    • un groupe -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)xCO-NR8R9 ou -(CH2)x-NR8-COR9, dans lesquels x = 0, 1, 2, 3 ou 4 et R8 et R9 sont tels que définis ci-dessus,
    • un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle,
    • un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle, -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9, -SO2-alkyle, -SO2-cycloalkyle, -SO2-hétérocycloalkyle, -SO2-aryle, -SO2-hétéroaryle, -SO2-alkylaryle, -SO2-alkylhétéroaryle ou -SO2-NR8R9, où R8 et R9 sont tels que définis ci-dessus,
    • ou bien R10 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons,
    R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou bien R et R' peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.
    les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles et hétéroaryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les groupes R, R', - OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR'
  • (2) un groupe de formule -A-R18, -A-CH=N-R19, -A-N(R20)-A'-R19, -A-CO-N(R20)-A'-R19, -A-CH(NH2)-R19 ou -A-N(R20)-COO-A', dans lesquels A et A' représentent un groupe alkyle linéaire ou ramifié, R18 représente un atome d'halogène ou un groupe -NH2, hydroxyle ou phényle, R19 représente un atome d'hydrogène ou un groupe hydroxyle, phényle, benzyle ou hétéroaryle, et R20 représente un atome d'hydrogène ou un groupe benzyle,
  • (3) un groupe de formule (d) :
    Figure imgb0003
     éventuellement substitué, en des positions quelconques, par 1 à 4 groupes R7, identiques ou différents les uns des autres, tels que définis ci-dessus et dans laquelle r est égal à 1, 2 ou 3, s est égal à 0 ou 1, et l'un de U, V ou W représente un atome d'azote, les autres parmi U, V et W représentant des chaînons méthylène (c'est-à-dire des chaînons -CH2- pour V et W et un chaînon -CH- pour U), ou
  • (4) un groupe -(CH2)r-hétéroaryle, où r est égal à 1, 2 ou 3.
In view of the constant need to improve the existing therapies for the pathologies mentioned above, the inventors have set themselves the goal of providing new melanocortin receptor agonist compounds. The subject of the present invention is compounds corresponding to formula (I)
Figure imgb0001
 in which :
  • R a and R a , which are identical or different from one another, represent a hydrogen atom or an alkyl or cycloalkyl group,
  • R 1 represents a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl or aryl group,
  • R 2 represents a group of formula - (CH 2 ) x (CO) yY or - (CO) y - (CH 2 ) x -Y, in which:
    • x = 0, 1, 2, 3 or 4,
    • y = 0 or 1,
    • Y represents a hydrogen atom or a hydroxyl, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl or -NR 11 R 12 group , Y being different from a hydrogen atom when x = y = 0,
    • R 11 and R 12 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl, alkoxy or -NR 13 R 14 group , or R 11 and R 12 together form, with nitrogen atom to which they are attached, a mono-or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any positions by 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups. By way of examples of such cyclic structures, mention may be made of pyrrolidinyl, morpholinyl, pyrrolinyl and isoindolinyl groups, etc.
    • R 13 and R 14 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or else R 13 and R 14 form together with the nitrogen atom to which they are attached, a mono- or bicyclic as defined above,
  • R 3 represents 1 to 3 groups, identical or different from each other, located in any positions of the nucleus to which they are attached and selected from halogen atoms and alkyl, cycloalkyl groups, -OR, -NRR ', - CO-NRR ', -NR-COR', -NR-CO-NRR ', -NR-COOR', -NO 2 , -CN and -COOR, where R and R 'are as defined below,
  • R 5 represents a hydrogen atom or an alkyl or cycloalkyl group,
  • R 4 is chosen from:
    1. (1) a group of formula (a), (b) or (c) optionally substituted by an oxo group:
      Figure imgb0002
       wherein each of the rings of formulas (a), (b) and (c) may be substituted, at any position, with 1 to 4 R 7 groups, the same or different from each other, and wherein:
      • a = 0, 1, 2 or 3,
      • p = 0, 1, 2 or 3,
      • m = 0, 1 or 2,
      • X represents an oxygen or sulfur atom or a -C (R 6 ) (R 7 ) - or -N (R 10 ) - chain,
    R 6 is chosen from:
    • a hydrogen atom, a halogen atom
    • a group - (CH 2 ) x OR 8 , - (CH 2 ) x COOR 8 , - (CH 2 ) x NR 8 R 9 , - (CH 2 ) x -CO-NR 8 R 9 or - (CH 2) x -NR 8 -COR 9 , in which x = 0, 1, 2, 3 or 4 and R 8 and R 9 are as defined below,
    • alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl or -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 ,
    • a cycloalkyl or heterocycloalkyl group fused or not located in the spiro position on the ring of formula (a) to which it is attached,
    • a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
    R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NR-COOR ', -NO 2 , -CN and -COOR, where R and R' are as defined below,
    • R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls -SO 2 -cycloalkyls, -SO 2 -heterocycloalkyls, -SO 2 -aryls, -SO 2 - heteroaryls, -SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ', -COOR, -CO-NRR', -CS-NRR 'and - (CH 2 ) x -OR, where x = 0, 1, 2, 3 or 4 and R and R 'are as defined below, the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more groups selected from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR-CO-R', -NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR '
    or R 8 and R 9 together form cycloalkyl or heterocycloalkyl;
    R 10 is chosen from:
    • a hydrogen atom,
    • a group - (CH 2 ) x -OR 8 , - (CH 2 ) x -COOR 8 , - (CH 2 ) x -NR 8 R 9 , - (CH 2 ) x CO-NR 8 R 9 or - (CH 2) 2 ) x -NR 8 -COR 9 , in which x = 0, 1, 2, 3 or 4 and R 8 and R 9 are as defined above,
    • a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
    • alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl , -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 , -SO 2 -alkyl, -SO 2 -cycloalkyl, -SO 2 -heterocycloalkyl, -SO 2 -aryl, -SO 2 -heteroaryl, -SO 2 -alkylaryl, -SO 2 -alkylheteroaryl or -SO 2 -NR 8 R 9 , where R 8 and R 9 are as defined above,
    • or R 10 forms, with the nitrogen atom to which it is attached and a carbon atom at any position in the ring structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 links,
    R and R ' independently of one another are hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, or R and R' may together form cycloalkyl or heterocycloalkyl.
    the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted with one or more groups chosen from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR-CO-R', - NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR '
  • (2) a group of formula -AR 18 , -A-CH = NR 19 , -AN (R 20 ) -A'-R 19 , -A-CO-N (R 20 ) -A'-R 19 , - A-CH (NH 2 ) -R 19 or -AN (R 20 ) -COO-A ', wherein A and A' represent a linear or branched alkyl group, R 18 represents a halogen atom or a group -NH 2 , hydroxyl or phenyl, R 19 represents a hydrogen atom or a hydroxyl, phenyl, benzyl or heteroaryl group, and R 20 represents a hydrogen atom or a benzyl group,
  • (3) a group of formula (d):
    Figure imgb0003
     optionally substituted, at any position, with 1 to 4 groups R 7 , identical to or different from each other, as defined above and in which r is equal to 1, 2 or 3, s is equal to 0 or 1; and one of U, V or W represents a nitrogen atom, the others of U, V and W represent methylene links (i.e., -CH 2 - links for V and W and a link -CH- for U), or
  • (4) a - (CH 2 ) r -heteroaryl group, where r is 1, 2 or 3.

Les composés de formule (I) comportent au moins un atome de carbone asymétrique. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, font partie de l'invention.The compounds of formula (I) comprise at least one asymmetric carbon atom. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

Parmi les composés de formule (I) objets de l'invention, on préfère ceux dans lesquels l'atome de carbone, identifié par l'astérisque * dans la formule suivante, présente une configuration (R) :

Figure imgb0004
Among the compounds of formula (I) which are subjects of the invention, those in which the carbon atom, identified by the asterisk * in the following formula, has a configuration (R) are preferred:
Figure imgb0004

Les composés de formule (I) selon l'invention peuvent également exister sous forme de mélanges de conformères, qui font également partie de l'invention. Ils peuvent en outre exister sous forme d'isomères cis ou trans, ou sous forme d'isomères endo ou exo. Ces isomères ainsi que leur mélange, font partie de l'invention.The compounds of formula (I) according to the invention may also exist in the form of mixtures of conformers, which are also part of the invention. They can additionally exist in the form of cis or trans isomers, or in the form of endo or exo isomers. These isomers and their mixture are part of the invention.

A cet égard, le noyau tropane des composés de formule (I) selon l'invention présente avantageusement une configuration endo, telle que représentée ci-dessous :

Figure imgb0005
In this respect, the tropane nucleus of the compounds of formula (I) according to the invention advantageously has an endo configuration, as represented below:
Figure imgb0005

Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font partie de l'invention.The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

Ces sels sont avantageusement préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (I) font également partie de l'invention.These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

Les composés de formule (I) peuvent également exister sous forme d'hydrates ou de solvats, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvats font également partie de l'invention.The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.

Dans le cadre de la présente invention, et sauf mention différente dans le texte, on entend par:

  • un atome d'halogène : un fluor, un chlore, un brome ou un iode ;
    un groupe alkyle: un groupe aliphatique saturé ou insaturé (c'est-à-dire comprenant entre 1 et 3 insaturations de type éthylénique ou acétylénique), comprenant de 1 à 6 atomes de carbone, linéaire, cyclique ou ramifié. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, pentyle, neo-pentyle, etc... et les groupes cycloalkyles définis ci-après, ainsi que les groupes alkyles cyclisés seulement en partie, tel que le groupe méthyl-cyclopropyle. Un tel groupe alkyle peut être substitué par 1 ou plusieurs groupes (par exemple par 1 à 6 groupes) choisis parmi les atomes d'halogène (résultant par exemple en un groupe -CF3) et les groupes R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et - COOR, OCOR, COR, OCONRR', NRCOOR', où R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène, un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou hétérocycloalkyle ,
  • un groupe cycloalkyle : un groupe alkyle cyclique comprenant entre 3 et 8 atomes de carbone, tous les atomes de carbone étant engagés dans la structure cyclique. A titre d'exemples, on peut citer les groupes cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, etc ... Un tel groupe cycloalkyle peut être substitué comme décrit ci-dessus pour le groupe alkyle ;
  • un groupe hétérocycloalkyle : un groupe cycloalkyle tel que défini ci-dessus, comprenant en outre entre 1 et 4 hétéroatomes, tels que l'azote, l'oxygène et/ou le soufre. Un tel groupe hétérocycloalkyle peut-être substitué comme décrit ci-dessus pour le groupe cycloalkyle et peut comprendre une ou plusieurs, par exemple 1 ou 2, insaturations éthyléniques ou acétyléniques. A titre d'exemples de groupes hétérocycloalkyles, on peut citer les groupes pipéridinyle et tétrahydropyrane ;
  • un groupe alcoxy : un radical -O-alkyle, où le groupe alkyle est tel que précédemment défini ;
  • un groupe aryle : un groupe aromatique cyclique comprenant entre 5 et 10 chaînons, par exemple un groupe phényle. Un tel groupe aryle peut être substitué par 1 ou plusieurs groupes (par exemple par 1 à 6 groupes) choisis parmi les atomes d'halogène (résultant par exemple en un groupe -CF3) et les groupes alkyles, R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, COR et -COOR, où R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène, un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle ou peuvent former ensemble un cycloalkyle ou hétérocycloalkyle;
  • un groupe alkylaryle : un groupe alkyle tel que défini ci-dessus, lui-même substitué par un groupe aryle tel que défini ci-dessus. Un tel groupe alkylaryle est par exemple un groupe benzyle ;
  • un groupe hétéroaryle : un groupe aromatique cyclique comprenant entre 5 et 10 chaînons et comprenant entre 1 et 6 hétéroatomes, tels que l'azote, l'oxygène et/ou le soufre. A titre d'exemple on peut citer le groupe pyridinyle et le groupe fyryle. Un tel groupe hétéroaryle peut-être substitué comme décrit ci-dessus pour le groupe aryle
  • un groupe alkylhétéroaryle : un groupe alkyle tel que défini ci-dessus, lui-même substitué par un groupe hétéroaryle tel que défini ci-dessus.
In the context of the present invention, and unless otherwise stated in the text, the following terms mean:
  • a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
    an alkyl group: a saturated or unsaturated aliphatic group (that is to say comprising between 1 and 3 ethylenic or acetylenic type unsaturations), comprising from 1 to 6 carbon atoms, linear, cyclic or branched. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl, etc. groups and the cycloalkyl groups defined below, as well as cyclized alkyl groups. only in part, such as the methyl-cyclopropyl group. Such an alkyl group may be substituted with 1 or more groups (for example with 1 to 6 groups) chosen from halogen atoms (resulting for example in a group -CF 3 ) and the groups R, R ', -OR, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR', where R and R 'independently of one another represent a hydrogen atom, an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or heterocycloalkyl,
  • a cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being engaged in the ring structure. By way of examples, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, etc. Such a cycloalkyl group may be substituted as described above for the alkyl group;
  • a heterocycloalkyl group: a cycloalkyl group as defined above, further comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen and / or sulfur. Such a heterocycloalkyl group may be substituted as described above for the cycloalkyl group and may include one or more, for example 1 or 2, ethylenic or acetylenic unsaturations. As examples of heterocycloalkyl groups, mention may be made of piperidinyl and tetrahydropyran groups;
  • an alkoxy group: an -O-alkyl radical, where the alkyl group is as previously defined;
  • an aryl group: a cyclic aromatic group comprising between 5 and 10 chain members, for example a phenyl group. Such an aryl group may be substituted with 1 or more groups (for example with 1 to 6 groups) selected from halogen atoms (resulting for example in a group -CF 3 ) and alkyl groups, R, R ', - OR, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN, COR and -COOR, where R and R 'independently represent one on the other a hydrogen atom, an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group or may together form a cycloalkyl or heterocycloalkyl;
  • an alkylaryl group: an alkyl group as defined above, itself substituted with an aryl group as defined above. Such an alkylaryl group is, for example, a benzyl group;
  • a heteroaryl group: a cyclic aromatic group comprising between 5 and 10 members and comprising between 1 and 6 heteroatoms, such as nitrogen, oxygen and / or sulfur. By way of example, mention may be made of the pyridinyl group and the erythryl group. Such a heteroaryl group may be substituted as described above for the aryl group
  • an alkylheteroaryl group: an alkyl group as defined above, itself substituted with a heteroaryl group as defined above.

Parmi les composés de formule (I) objets de l'invention, on peut citer ceux dans lesquels Ra, Ra', R2, R3, R4 et R5 sont tels que définis ci-dessus et R1 représente un groupe alkyle, cycloalkyle, hétérocycloalkyle ou phényle. De façon avantageuse, R1 représente un groupe cycloalkyle, tel qu'un groupe cyclohexyle.Among the compounds of formula (I) which are subjects of the invention, mention may be made of those in which R a , R a ' , R 2 , R 3 , R 4 and R 5 are as defined above and R 1 represents a alkyl, cycloalkyl, heterocycloalkyl or phenyl group. Advantageously, R 1 represents a cycloalkyl group, such as a cyclohexyl group.

Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra', R1, R3, R4 et R5 sont tels que définis ci-dessus et R2 est choisi parmi les groupes suivants : -CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-aryle, -CO-hétéroaryle, -CO-(CH2)x'-NR16R17, -(CH2)x-NR16R17, -(CH2)x-OH, -(CH2)x-aryle, -(CH2)x-hétéroaryle, -(CH2)x'-CO-R15 et -(CH2)x'-CO-NR16R17, dans lesquels :

  • x = 0, 1, 2, 3 ou 4 et x' = 1, 2, 3 ou 4,
  • R15 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, et
  • R16 et R17, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien R16 et R17 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy.
Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R a , R a ' , R 1 , R 3 , R 4 and R 5 are as defined above and R 2 is selected from the following groups: -CO-R 15 , -CO-NR 16 R 17 , -CO-NR 15 -NR 16 R 17 , -CO-aryl, -CO-heteroaryl, -CO- (CH 2 ) x ' -NR 16 R 17 , - (CH 2 ) x -NR 16 R 17 , - (CH 2 ) x -OH, - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) x ' -CO-R 15 and - (CH 2 ) x' -CO-NR 16 R 17 , in which:
  • x = 0, 1, 2, 3 or 4 and x '= 1, 2, 3 or 4,
  • R 15 represents a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, and
  • R 16 and R 17 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or else R 16 and R 17 form together with the nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any position by 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups.

Parmi les composés de formule (I) objets de l'invention, on peut plus particulièrement citer ceux dans lesquels R2 représente un groupe -CO-NR16R17, où R16 et R17 représentent des groupes alkyles ou alcoxy. R2 représente avantageusement un groupe -CO-NR16R17, ou R16 et R17 représentent des groupes alkyles.Among the compounds of formula (I) which are subjects of the invention, mention may be made more particularly of those in which R 2 represents a group -CO-NR 16 R 17 , where R 16 and R 17 represent alkyl or alkoxy groups. R 2 advantageously represents a -CO-NR 16 R 17 group , or R 16 and R 17 represent alkyl groups.

Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra', R1, R2, R4 et R5 sont tels que définis ci-dessus et R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, choisis parmi les atomes d'halogène. Avantageusement, R3 représente un seul groupe, de préférence un atome de chlore.Among the compounds of formula (I) that are subjects of the invention, mention may also be made of those in which R a , R a ' , R 1 , R 2 , R 4 and R 5 are as defined above and R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms. Advantageously, R 3 represents a single group, preferably a chlorine atom.

Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra', R1, R2, R3 et R5 sont tels que définis ci-dessus et R4 est choisi parmi:

  1. (1) un groupe de formule (a-1), (a-2), (a-3), (a-4) ou (b-1) ci-dessous :
    Figure imgb0006
     dans lesquelles chacun des cycles de formules (a-1), (a-2), (a-3), (a-4) et (b-1) peut être substitué, en des positions quelconques, par 1 à 4 groupes R7, identiques ou différents les uns des autres, tels que définis ci-avant, et dans lesquelles a' = 0 ou 1, p = 0, 1, 2 ou 3; p' = 0 ou 1, m = 0, 1 ou 2 et R6 et R10 sont tels que définis ci-avant,
  2. (2) un groupe de formule -A-R18 ou -A-CH=N-R19, où A, R18 et R19 sont tels que définis ci-avant,
  3. (3) un groupe de formule (d) telle que définie ci-avant :
    Figure imgb0007
  4. (4) un groupe -(CH2)r-furyle ou -(CH2)r-pyridinyle, où r est égal à 1, 2 ou 3.
Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R a , R a ' , R 1 , R 2 , R 3 and R 5 are as defined above and R 4 is chosen from:
  1. (1) a group of formula (a-1), (a-2), (a-3), (a-4) or (b-1) below:
    Figure imgb0006
     wherein each of the rings of formulas (a-1), (a-2), (a-3), (a-4) and (b-1) may be substituted at any position by 1 to 4 groups R 7 , which are identical to or different from each other, as defined above, and in which a '= 0 or 1, p = 0, 1, 2 or 3; p '= 0 or 1, m = 0, 1 or 2 and R 6 and R 10 are as defined above,
  2. (2) a group of formula -AR 18 or -A-CH = NR 19 , where A, R 18 and R 19 are as defined above,
  3. (3) a group of formula (d) as defined above:
    Figure imgb0007
  4. (4) a - (CH 2 ) r -furyl or - (CH 2 ) r -pyridinyl group, where r is 1, 2 or 3.

Dans les groupes de formules (a-1), (a-2), (a-3), (a-4) ou (b-1) ci-dessus, on peut en particulier citer ceux pour lesquels R6 représente un groupement -NH2 ou phényle, R7 représente un atome d'hydrogène ou un groupe hydroxyle et R10 représente un atome d'hydrogène ou un groupe aryle, alkylaryle ou forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a-1), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons. Avantageusement, R10 représente un atome d'hydrogène dans le groupe de formule (b-1) et, dans le groupe de formule (a-1), un atome d'hydrogène ou un groupe phényle, benzyle ou forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a-1), mais non adjacent audit atome d'azote, un pont comprenant 4 chaînons.In the groups of formulas (a-1), (a-2), (a-3), (a-4) or (b-1) above, mention may be made in particular of those for which R 6 represents a -NH 2 or phenyl group, R 7 represents a hydrogen atom or a hydroxyl group and R 10 represents a hydrogen atom or an aryl, alkylaryl or form, with the nitrogen atom to which it is attached and a a carbon atom at any position in the ring structure of formula (a-1), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members. Advantageously, R 10 represents a hydrogen atom in the group of formula (b-1) and, in the group of formula (a-1), a hydrogen atom or a phenyl, benzyl or form group, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of formula (a-1), but not adjacent to said nitrogen atom, a bridge comprising 4 links.

Parmi les composés de formule (I) objets de l'invention, on peut encore citer ceux dans lesquels. Ra, Ra', R1, R2, R3 et R5 sont tels que définis ci-dessus et R4 est choisi parmi :

  1. (1) un groupe de formule (a-5), (a-6) ou (b-2) ci-dessous :
    Figure imgb0008
     dans lesquelles chacun des cycles de formules (a-5), (a-6) et (b-2) peut être substitué, en des positions quelconques, par 1 à 4 groupes R7, identiques ou différents les uns des autres, tels que définis ci-avant, et dans lesquelles a' = 0 ou 1, p'. = 0 ou 1, m = 0, 1 ou 2 et R6 et R10 sont tels que définis ci-avant,
  2. (2) un groupe de formule -A-R18 ou -A-CH=N-R19, où A, R18 et R19 sont tels que définis ci-avant,
  3. (3) un groupe de formule (d-1), où r = 1, 2 ou 3 :
    Figure imgb0009
  4. (4) un groupe -(CH2)r-furyle ou -(CH2)r-pyridinyle, où r est égal à 1, 2 ou 3.
Among the compounds of formula (I) that are the subject of the invention, mention may also be made of those in which R a , R a ' , R 1 , R 2 , R 3 and R 5 are as defined above and R 4 is chosen from:
  1. (1) a group of formula (a-5), (a-6) or (b-2) below:
    Figure imgb0008
     wherein each of the rings of formulas (a-5), (a-6) and (b-2) may be substituted, at any position, with 1 to 4 groups R 7 , which are identical or different from one another, such as as defined above, and in which a '= 0 or 1, p'. = 0 or 1, m = 0, 1 or 2 and R 6 and R 10 are as defined above,
  2. (2) a group of formula -AR 18 or -A-CH = NR 19 , where A, R 18 and R 19 are such that defined above,
  3. (3) a group of formula (d-1), where r = 1, 2 or 3:
    Figure imgb0009
  4. (4) a - (CH 2 ) r -furyl or - (CH 2 ) r -pyridinyl group, where r is 1, 2 or 3.

Dans les groupes de formules (a-5), (a-6) et (b-2) ci-dessus, on peut en particulier citer ceux pour lesquels R6 représente un groupement -NH2 ou phényle, R7 représente un atome d'hydrogène ou un groupe hydroxyle et R10 représente un atome d'hydrogène ou un groupe aryle, alkylaryle ou forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a-5), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons. Avantageusement, R10 représente un atome d'hydrogène dans le groupe de formule (b-2) et, dans le groupe de formule (a-5), un atome d'hydrogène ou un groupe phényle ou benzyle ou forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de formule (a-5), mais non adjacent audit atome d'azote, un pont comprenant 4 chaînons.In the groups of formulas (a-5), (a-6) and (b-2) above, mention may be made especially of those for which R 6 represents a group -NH 2 or phenyl, R 7 represents an atom of hydrogen or a hydroxyl group and R 10 represents a hydrogen atom or an aryl, alkylaryl or form group, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of the formula (a-5), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members. Advantageously, R 10 represents a hydrogen atom in the group of formula (b-2) and, in the group of formula (a-5), a hydrogen atom or a phenyl or benzyl group or forms, with the nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure of formula (a-5), but not adjacent to said nitrogen atom, a bridge comprising 4 links.

Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra', R1, R2, R3 et R4 sont tels que définis ci-dessus et R5 représente un atome d'hydrogène ou un groupe alkyle comprenant de 1 à 4 atomes de carbone. R5 représente de préférence un atome d'hydrogène.Among the compounds of formula (I) that are the subject of the invention, mention may also be made of those in which R a , R a ' , R 1 , R 2 , R 3 and R 4 are as defined above and R 5 represents a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms. R 5 preferably represents a hydrogen atom.

Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels R1, R2, R3, R4 et R5 sont tels que définis ci-dessus et Ra et Ra' représentent des atomes d'hydrogène ou des groupes alkyles comprenant de 1 à 4 atomes de carbone. Avantageusement, Ra et Ra' représentent indépendamment l'un de l'autre des atomes d'hydrogène ou des groupes méthyles. De façon préférée, Ra = Ra' = H.Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R 1 , R 2 , R 3 , R 4 and R 5 are as defined above and R a and R a ' represent hydrogen atoms or alkyl groups having 1 to 4 carbon atoms. Advantageously, R a and R a ' represent, independently of one another, hydrogen atoms or methyl groups. Preferably, R a = R a ' = H.

Parmi les groupes R6 définis précédemment, on peut notamment citer ceux dans lesquels R6 représente un atome d'hydrogène ou un groupe -NR8R9 ou aryle, dans lesquels R8 et R9 représentent un atome d'hydrogène ou un groupe alkyle. On peut également citer les groupes R6 représentant un atome d'hydrogène ou un groupe -NH2 ou phényle.Among the groups R 6 defined above, there may be mentioned those in which R 6 represents a hydrogen atom or a group -NR 8 R 9 or aryl, in which R 8 and R 9 represent a hydrogen atom or an alkyl group. There may also be mentioned groups R 6 representing a hydrogen atom or a group -NH 2 or phenyl.

Parmi les groupes R7 définis précédemment, on peut notamment citer ceux dans lesquels R7 représente un atome d'hydrogène ou d'halogène ou un groupe alkyle, hydroxyle (correspondant à un groupe -OR, où R représente un atome d'hydrogène) ou alcoxy (correspondant à un groupe -OR, où R représente un groupe alkyle). R7 représente avantageusement un atome d'hydrogène ou un groupe hydroxyle.Among the groups R 7 defined above, there may be mentioned those in which R 7 represents a hydrogen or halogen atom or an alkyl or hydroxyl group (corresponding to a group -OR, where R represents a hydrogen atom) or alkoxy (corresponding to a group -OR, where R represents an alkyl group). R 7 advantageously represents a hydrogen atom or a hydroxyl group.

Parmi les groupes R8 et R9 définis précédemment, on peut notamment citer ceux dans lesquels R8 et R9 représentent un atome d'hydrogène ou un groupe alkyle.Among the groups R 8 and R 9 defined above, there may be mentioned those in which R 8 and R 9 represent a hydrogen atom or an alkyl group.

Parmi les groupes R10 définis précédemment, on peut notamment citer ceux dans lesquels R10 représente un atome d'hydrogène ou un groupe aryle (tel qu'un groupe phényle) ou alkylaryle (tel qu'un groupe benzyle), ou bien R10 forme, avec l'atome d'azote qui le porte et un atome de carbone situé en une position quelconque de la structure cyclique à laquelle il est rattaché, mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons.Among the groups R 10 defined above, there may be mentioned those in which R 10 represents a hydrogen atom or an aryl group (such as a phenyl group) or alkylaryl (such as a benzyl group), or R 10 forms, with the nitrogen atom that carries it and a carbon atom located at any position of the ring structure to which it is attached, but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members.

Parmi les groupes R et R' définis précédemment, on peut notamment citer ceux dans lesquels R et R' représentent un atome d'hydrogène ou un groupe alkyle.Among the groups R and R 'defined above, there may be mentioned those in which R and R' represent a hydrogen atom or an alkyl group.

Chacune des définitions données ci-avant pour les groupes Ra, Ra', R1, R2, R3, R4, R5, R6, R7, F8, R9, R10, R et R' peuvent se combiner les unes avec les autres de façon à obtenir différents sous-groupes de composés de formule (I) selon la présente invention.Each of the definitions given above for the groups R a , R a ' , R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , F 8 , R 9 , R 10 , R and R can be combined with each other so as to obtain different subgroups of compounds of formula (I) according to the present invention.

On peut par exemple citer un sous-groupe de composés de formule (I) selon l'invention, dans lequel :

  • Ra et Ra' représentent indépendamment l'un de l'autre des atomes d'hydrogène
ou des groupes méthyles,
  • R1 représente un groupe alkyle, cycloalkyle ou hétérocycloalkyle,
  • R2 est choisi parmi les groupes suivants : -CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-aryle, -CO-hétéroaryle, -CO-(CH2)x-NR16R17, -(CH2)x-NR16R17, -(CH2)x-OH, -(CH2)x-aryle, -(CH2)x-hétéroaryle, -(CH2)x'-CO-R15 et -(CH2)x'-CO-NR16R17, dans lesquels :
    • x = 0, 1, 2, 3 ou 4 et x' = 1, 2, 3 ou 4,
    • R15 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, et
    • R16 et R17, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien R16 et R17 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué, en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy,
  • R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, choisis parmi les atomes d'halogène,
  • R4 est choisi parmi :
    1. (1) un groupe de formule (a-1), (a-2), (a-3), (a-4) ou (b-1) ci-dessous :
      Figure imgb0010
       dans lesquelles chacun des cycles de formules (a-1), (a-2), (a-3), (a-4) et (b-1) peut être substitué; en des positions quelconques, par 1 à 4 groupes R7; identiques ou différents les uns des autres, tels que définis ci-avant, et dans lesquelles a' = 0 ou 1, p = 0, 1, 2 ou 3, p' = 0 ou 1, m = 0, 1 ou 2 et R6 et R10 sont tels que définis ci-avant,
    2. (2) un groupe de formule -A-R18 ou -A-CH=N-R19, où A, R18 et R19 sont tels que définis ci-avant,
    3. (3) un groupe de formule (d) telle que définie ci-avant :
      Figure imgb0011
    4. (4) un groupe -(CH2)r-furyle ou -(CH2)r-pyridinyle, où r est égal à 1, 2 ou 3, et
    - R5 représente un atome d'hydrogène.
For example, a subgroup of compounds of formula (I) according to the invention may be mentioned, in which:
  • R a and R a ' independently of one another represent hydrogen atoms
or methyl groups,
  • R 1 represents an alkyl, cycloalkyl or heterocycloalkyl group,
  • R 2 is selected from the following groups: -CO-R 15 , -CO-NR 16 R 17 , -CO-NR 15 -NR 16 R 17 , -CO-aryl, -CO-heteroaryl, -CO- (CH 2 ) x -NR 16 R 17, - (CH 2) x -NR 16 R 17, - (CH 2) x -OH, - (CH 2) x -aryl, - (CH 2) x -heteroaryl, - (CH 2 ) x ' -CO-R 15 and - (CH 2 ) x' -CO-NR 16 R 17 , wherein:
    • x = 0, 1, 2, 3 or 4 and x '= 1, 2, 3 or 4,
    • R 15 represents a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, and
    • R 16 and R 17 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or else R 16 and R 17 form together with the nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted, at any position by 1 to 3 groups chosen from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups,
  • R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms,
  • R 4 is chosen from:
    1. (1) a group of formula (a-1), (a-2), (a-3), (a-4) or (b-1) below:
      Figure imgb0010
       wherein each of the rings of formulas (a-1), (a-2), (a-3), (a-4) and (b-1) may be substituted; in any positions, with 1 to 4 groups R 7 ; identical or different from each other, as defined above, and in which a '= 0 or 1, p = 0, 1, 2 or 3, p' = 0 or 1, m = 0, 1 or 2 and R 6 and R 10 are as defined above,
    2. (2) a group of formula -AR 18 or -A-CH = NR 19 , where A, R 18 and R 19 are as defined above,
    3. (3) a group of formula (d) as defined above:
      Figure imgb0011
    4. (4) a - (CH 2 ) r -furyl or - (CH 2 ) r -pyridinyl group, where r is 1, 2 or 3, and
    - R 5 represents a hydrogen atom.

Selon un autre objet l'invention se rapporte aux composés préférés en particulier les composés de configuration endo, dont les noms suivent :

  • Dans les listes qui suivent les chiffres devant les nomenclatures des produits correpondent aux n° d'exemple des composés du tableau
    • 1 : N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 2: N-[8-(4-chloro-N-piperidin-3-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N cyclohexyl-N',N'-diethylurea
    • 3: N-{8-[N-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 4: N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 5: N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 6: N-{8-[4-chloro-N-(piperidin-4-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N,N'-diethylurea
    • 7: N-{8-[4-chloro-N-(piperidin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    • 8: N-{8-[4-chloro-N-(tetrahydro-3-thienyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 9: N-[8-(N-1-azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 10: N-[8-(N-azepan-4-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 11: N-[8-(4,chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 12: N-[8-(4-chloro-N-{[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8- - azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 13: N-[8-(4-chloro-N-{((2R,4S)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 14 : N-{8-(4-chloro-N-(1-phenylpiperidin-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N,N-diethylurea
    • 15: N-(8-{N-[(1-benzylpyrrolidin-3-yl)methyl]-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N,N-diethylurea
    • 16: N-[8-(4-chloro-N-pyrrolidin-3-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N cyclohexyl-N',N'-diethylurea
    • 17: N-(8-{4-chloro-N-[4-(4-hydroxyphenyl)cyclohexyl]-D-phenylanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N,N-diethylurea
    • 18: N-(8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 19: N-{8-[N-(3-aminopropyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 20: N-(8-{4-chloro-N-[(2E)-2-(hydroxyimino)-1-methylethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    • 21: N-{8-[4-chloro-N-(2-fluoro-1-methylethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 22: N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    • 23: N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 24: N-{8-[4-chloro-N-(2-furylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    • 25: N-(8-{4-chloro-N-[(2R)-pyrrolidin-2-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    • 26: N-(8-{4-chloro-N-[(2S)-pyrrolidin-2-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    • 27: N-[8-(N-azetidin-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    • 28: N-(8-{N-[(1-benzylpyrrolidin-3-yl)methyl]-4-chloro-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
According to another object, the invention relates to preferred compounds, in particular compounds of endo configuration, whose names follow:
  • In the lists that follow the figures in front of the product nomenclatures correspond to the example numbers of the compounds of the table
    • 1: N - [8- (4-chloro- N -piperidin-4-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] - N- cyclohexyl- N ', N' - diethylurea
    • 2: N - [8- (4-chloro- N -piperidin-3-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N cyclohexyl- N ', N ' -diethylurea
    • 3: N - {8- [ N - (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' - diethylurea
    • 4: N - {8- [4-chloro- N - (tetrahydro-2 H -pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl - N ', N ' -diethylurea
    • 5: N - [8- ( N -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N - cyclohexyl- N ', N ' -diethylurea
    • 6: N - {8- [4-chloro- N - (piperidin-4-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N , N ' -diethylurea
    • 7: N - {8- [4-chloro- N - (piperidin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl) -N- cyclohexyl- N ', N '-diethylurea
    • 8: N - {8- [4-chloro- N - (tetrahydro-3-thienyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ' , N ' -diethylurea
    • 9: N - [8- ( N- 1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N - cyclohexyl- N ', N ' -diethylurea
    • 10: N - [8- (N -azepan-4-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] - N- cyclohexyl- N ', N' - diethylurea
    • 11: N - [8- (4, chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct 3-yl] - N -cyclohexyl- N ', N' -diethylurea
    • 12: N - [8- (4-chloro- N - {[(2 R , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct -3-yl] - N -cyclohexyl- N ' , N' -diethylurea
    • 13: N - [8- (4-chloro- N - {((2 R , 4 S ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct- 3-yl] - N -cyclohexyl- N ' , N' -diethylurea
    • 14: N - {8- (4-chloro- N - (1-phenylpiperidin-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N , N- diethylurea
    • 15: N - (8- { N - [(1-Benzylpyrrolidin-3-yl) methyl] -4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl) -N- cyclohexyl - N , N- diethylurea
    • 16: N - [8- (4-chloro- N -pyrrolidin-3-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N cyclohexyl- N ', N' -diethylurea
    • 17: N - (8- {4-chloro- N - [4- (4-hydroxyphenyl) cyclohexyl] -D-phenylanyl} -8-azabicyclo [3.2.1] oct-3-yl) -N- cyclohexyl- N , N- diethylurea
    • 18: N - (8- [ N - (2-aminoethyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' - diethylurea
    • 19: N - {8- [ N - (3-aminopropyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' - diethylurea
    • 20: N - (8- {4-chloro- N - [(2E) -2- (hydroxyimino) -1-methylethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) N -cyclohexyl- N ', N ' -diethylurea
    • 21: N - {8- [4-chloro- N - (2-fluoro-1-methylethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ' , N '-diethylurea
    • 22: N - (8- {4-chloro- N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3 -yl) - N -cyclohexyl- N ', N ' -diethylurea
    • 23: N- {8- [4-chloro- N - (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N '-diethylurea
    • 24: N - {8- [4-chloro- N - (2-furylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' - diethylurea
    • 25: N - (8- {4-chloro- N - [(2 R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) - N -cyclohexyl - N ', N ' -diethylurea
    • 26: N - (8- {4-chloro- N - [(2 S) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) - N -cyclohexyl - N ', N ' -diethylurea
    • 27: N - [8- (N -azetidin-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] - N- cyclohexyl- N ', N' - diethylurea
    • 28: N - (8- { N - [(1-Benzylpyrrolidin-3-yl) methyl] -4-chloro-D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) -N- cyclohexyl - N ', N ' -diethylurea

Dans ce qui suit, on entend par groupe protecteur (Pg) un groupe qui permet, d'une part, de protéger une fonction réactive telle qu'un hydroxy ou une amine pendant une synthèse et, d'autre part, de régénérer la fonction réactive intacte en fin de synthèse. Des exemples de groupes protecteurs ainsi que des méthodes de protection et de déprotection sont données dans « Protective Groups in Organic Synthesis », Green W. et al., 1999, 3rd Edition (John Wiley & Sons, Inc., New York ).In what follows, a protective group (Pg) is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis. Examples of protecting groups as well as methods of protection and deprotection are given in "Protective Groups in Organic Synthesis," Green W. et al., 1999, 3rd Edition (John Wiley & Sons, Inc., New York) ).

On entend par groupe partant (Lg), dans ce qui suit, un groupe pouvant être facilement clivé d'une molécule par rupture d'une liaison hétérolytique, avec départ d'une paire électronique. Ce groupe peut ainsi être remplacé facilement par un autre groupe lors d'une réaction de substitution, par exemple. De tels groupes partants sont, par exemple, les halogènes ou un groupe hydroxy activé tel qu'un mésyle, tosyle, triflate, acétyle, etc. Des exemples de groupes partants ainsi que des références pour leur préparation sont donnés dans « March's Advanced Organic Chemistry », J. March et al., 5th Edition, 2001, EMInter Ed .By leaving group (Lg) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of starting groups as well as references for their preparation are given in March's Advanced Organic Chemistry, J. March et al., 5th Edition, 2001, EMInter Ed .

On entend par groupement Boc un groupement t-butoxycarbonyl, Bn un groupement benzyle, CBz un groupement benzyloxycarbonyl, Fmoc un groupement 9-fluorenylmethyl-carbamate, et par h les heuresThe term "Boc group" means a t-butoxycarbonyl group, Bn a benzyl group, CBz a benzyloxycarbonyl group, Fmoc a 9-fluorenylmethyl-carbamate group, and by h the hours

Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé présenté dans le schéma 1.

Figure imgb0012
According to the invention, the compounds of general formula (I) can be prepared according to the process shown in Scheme 1.
Figure imgb0012

Selon le schéma 1, les composés de formule (IV) peuvent être préparés par couplage entre les intermédiaires de formule (II) et un aminoacide de formule (III) dont la fonction amine est protégée par un groupement protecteur Pg (par exemple un groupement Boc, CBz ou Fmoc), dans des conditions de couplage peptidique classiques, en utilisant par exemple comme agent couplant le dicyclocarbodiimide, le chlorhydrate du 1-(3-diméthylaminopropyl)-3-éthylcarbodiimide ou le bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, en présence ou non d'hydroxybenzo-triazole, et comme base la triéthylamine ou la diisopropyléthylamine dans un solvant tel que le dioxane, le dichlorométhane ou l'acétonitrile.According to Scheme 1, the compounds of formula (IV) may be prepared by coupling between the intermediates of formula (II) and an amino acid of formula (III), the amine function of which is protected by a protective group Pg (for example a Boc group) , CBz or Fmoc), under conventional peptide coupling conditions, for example using as the coupling agent dicyclocarbodiimide, hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in presence or absence of hydroxybenzo-triazole, and as base triethylamine or diisopropylethylamine in a solvent such as dioxane, dichloromethane or acetonitrile.

Les aminoacides de formule générale (III) sont disponibles commercialement ou peuvent être préparés par des méthodes décrites dans la littérature ( Williams, R.M., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989 ).The amino acids of general formula (III) are commercially available or can be prepared by methods described in the literature ( Williams, RM, Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989 ).

Les composés de formule (V) sont obtenus par déprotection de la fonction amine des composés de formule (IV), par des méthodes choisies parmi celles connues de l'Homme de l'art. Elles comprennent entre autres l'utilisation d'acide trifluoroacétique ou d'acide chlorhydrique dans le dichlorométhane, le dioxane, le tétrahydrofurane ou le diéthyléther dans le cas d'une protection par un groupement Boc, l'hydrogénation avec le métal approprié dans le méthanol ou l'éthanol dans le cas d'un CBz, et de pipéridine pour un groupement Fmoc, à des températures variant de -10°C à 100°C.The compounds of formula (V) are obtained by deprotection of the amine function of the compounds of formula (IV), by methods chosen from those known to those skilled in the art. They include inter alia the use of trifluoroacetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection with a Boc group, hydrogenation with the appropriate metal in methanol or ethanol in the case of a CBz, and piperidine for a Fmoc group, at temperatures ranging from -10 ° C to 100 ° C.

Dans une dernière étape, les composés de formule (I) sont obtenus par amination réductrice, réalisée en mettant les composés de formule (V) en présence d'un dérivé du groupe R4 de type oxo (aldéhyde ou cétone), en utilisant un réducteur tel que le borohydrure de sodium, le triacétoxyborohydrure de sodium ou le cyanoborohydrure de sodium, en présence ou non d'un acide de Bronsted (tel que l'acide chlorhydrique) ou de Lewis (tel que le tétraisopropoxyde de titane) dans un solvant tel que le dichloroéthane, le dichlorométhane, l'acide acétique ou le méthanol, à des températures comprises entre -10°C et 30°C. Les aldéhydes dérivés du groupe R4, quand ils ne sont pas commerciaux, sont préparés à partir des acides correspondants par des méthodes connues de l'Homme de l'art, par exemple par transformation en amide de Weinreb dans des conditions de couplage peptidique, puis par réduction de celui-ci par un hydrure tel que l'hydrure de lithium aluminium.In a final step, the compounds of formula (I) are obtained by reductive amination, carried out by bringing the compounds of formula (V) in the presence of a derivative of the R 4 group of the oxo (aldehyde or ketone) type, using a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or absence of a Bronsted acid (such as hydrochloric acid) or Lewis acid (such as titanium tetraisopropoxide) in a solvent such as dichloroethane, dichloromethane, acetic acid or methanol at temperatures between -10 ° C and 30 ° C. The aldehydes derived from the R 4 group, when they are not commercial, are prepared from the corresponding acids by methods known to those skilled in the art, for example by conversion into Weinreb amide under peptide coupling conditions. and then reducing it with a hydride such as lithium aluminum hydride.

Les dérivés du groupe R4 de type cétone ou aldéhyde peuvent être commerciaux ou obtenus par des méthodes connues de l'Homme de l'art, par exemple par acylation de la fonction amine ou hydroxyle libre du dérivé de type cétone.The R 4 ketone or aldehyde group derivatives may be commercial or obtained by methods known to those skilled in the art, for example by acylation of the amine or free hydroxyl function of the ketone derivative.

Les composés de formule générale (I), dans lesquels R4 répond aux formules (a), (b), (c), (d), -A-R18, -A-N(R20)-A'-R19 et -A-CH(NH2)-R19, peuvent également être préparés selon le procédé présenté dans le schéma 2.

Figure imgb0013
Compounds of general formula (I) in which R 4 corresponds to formulas (a), (b), (c), (d), -AR 18 , -AN (R 20 ) -A'-R 19 and A-CH (NH 2 ) -R 19 may also be prepared according to the process shown in Scheme 2.
Figure imgb0013

Selon le schéma 2, les composés de formule (V), obtenus comme décrit précédemment dans le schéma 1, sont mis en présence avec un dérivé du groupe R4 de type oxo (réaction d'amination réductrice, comme décrit ci-dessus en rapport avec le schéma 1), ledit groupe R4 portant un groupe Pg protecteur d'amine, pour donner les composés dé formule (VI). La fonction amine des composés de formule (VI) est ensuite déprotégée par des méthodes connues de l'Homme de l'art, comme décrit précédemment.According to Scheme 2, the compounds of formula (V), obtained as described previously in Scheme 1, are brought into contact with a derivative of the oxo-type R 4 group (reductive amination reaction, as described above in relation to with Scheme 1), said group R 4 carrying an amine protecting group Pg, to give the compounds of formula (VI). The amine function of the compounds of formula (VI) is then deprotected by methods known to those skilled in the art, as described above.

Alternativement, les composés de formule (VI) conduisant aux composés de formule (I) peuvent être préparés selon le procédé présenté dans le schéma 3

Figure imgb0014
Alternatively, the compounds of formula (VI) leading to the compounds of formula (I) may be prepared according to the process shown in scheme 3
Figure imgb0014

Selon le schéma 3, les composés de formule (VIII) peuvent être obtenus par amination réductrice, comme décrit précédemment, réalisée à partir des aminoacides de formule (VII). L'aminoacide de formule (VII) est disponible commercialement quand R5 = H, ou peut être préparé par des méthodes décrites dans la littérature ( Williams, R.M., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989 ). Dans les cas où R5 représente un groupe alkyle, les aminoacides de formule (VII) peuvent être préparés par alkylation de l'aminoacide commercial protégé sur la fonction amine, selon les méthodes d'alkylation connues de l'Homme de l'art.According to Scheme 3, the compounds of formula (VIII) can be obtained by reductive amination, as described above, carried out from the amino acids of formula (VII). The amino acid of formula (VII) is commercially available when R 5 = H, or can be prepared by methods described in the literature ( Williams, RM, Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989 ). In cases where R 5 represents an alkyl group, the amino acids of formula (VII) can be prepared by alkylation of the protected commercial amino acid on the amine function, according to the alkylation methods known to those skilled in the art.

Les composés de formule (IX) peuvent être synthétisés par saponification des esters de formule (VIII), par exemple en présence d'hydroxyde de sodium ou d'hydroxyde de lithium dans un solvant tel que le méthanol, le tétrahydrofurane ou l'eau, ou un mélange de ces solvants.The compounds of formula (IX) may be synthesized by saponification of the esters of formula (VIII), for example in the presence of sodium hydroxide or of lithium hydroxide in a solvent such as methanol, tetrahydrofuran or water, or a mixture of these solvents.

Les composés de formule générale (VI) peuvent être préparés par couplage peptidique entre les intermédiaires de formule (II) et l'aminoacide de formule (IX), dans des conditions de couplage peptidique telles que décrites dans le schéma 1.The compounds of general formula (VI) may be prepared by peptide coupling between the intermediates of formula (II) and the amino acid of formula (IX), under peptide coupling conditions as described in scheme 1.

Les composés de formulés (II) peuvent être obtenus selon le procédé présenté dans le schéma 4.

Figure imgb0015
The compounds of formula (II) can be obtained according to the process shown in scheme 4.
Figure imgb0015

Selon le schéma 4, les composés de formule (II) peuvent être préparés à partir du composé de formule (X) (où Pg est un groupement protecteur d'amine, tel que défini dans le schéma 1), après déprotection de la fonction amine par des méthodes choisies parmi celles connues de l'Homme de l'art, comme décrit précédemment.According to scheme 4, the compounds of formula (II) may be prepared from the compound of formula (X) (where Pg is an amine protecting group, as defined in scheme 1), after deprotection of the amine function by methods selected from those known to those skilled in the art, as described above.

Le composé de formule (X) est préparé selon les méthodes décrites dans la littérature ou connues de l'Homme de l'art, adaptées en fonction de la nature des groupes R1 et R2. Les schémas 5 à 9 ci-après présentent des exemples de préparation des composés de formule (X) selon différentes natures du groupe R2. Par exemple dans le cas où R2 représente un groupe -CO-R15, où R15 est tel que défini ci-avant, la préparation du composé (Xa) correspondant peut être effectuée selon le schéma 5.

Figure imgb0016
The compound of formula (X) is prepared according to the methods described in the literature or known to those skilled in the art, adapted according to the nature of the groups R 1 and R 2 . Diagrams 5 to 9 below show examples of the preparation of compounds of formula (X) according to different types of group R 2 . For example, in the case where R 2 represents a group -CO-R 15 , where R 15 is as defined above, the preparation of the corresponding compound (Xa) can be carried out according to scheme 5.
Figure imgb0016

Selon le schéma 5, les composés de formule (XI) peuvent être obtenus par amination réductrice, dans les conditions décrites précédemment, de la nortropanone dont la fonction amine est protégée (par exemple la Boc-nortropanone commerciale). On obtient ensuite les composés de formule (Xa) par réaction des composés de formule (XI) avec un chlorure d'acide de formule R15COCl, en présence d'une base organique telle que la triéthylamine ou la pyridine, dans un solvant tel que le dichlorométhane ou le tétrahydrofurane.According to Scheme 5, the compounds of formula (XI) can be obtained by reductive amination, under the conditions described above, of nortropanone. whose amine function is protected (eg commercial Boc-nortropanone). The compounds of formula (Xa) are then obtained by reacting the compounds of formula (XI) with an acid chloride of formula R 15 COCl, in the presence of an organic base such as triethylamine or pyridine, in a solvent such as than dichloromethane or tetrahydrofuran.

Le schéma 6 présente une voie de préparation des composés de formule (Xb) et (Xc), qui correspondent respectivement aux composés de formule (X) dans lesquels R2 représente un groupe -CO-NR16R17 et -CO-NR15-NR16R17, où R15, R16 et R17 sont tels que définis ci-avant.

Figure imgb0017
Scheme 6 shows a route of preparation of the compounds of formula (Xb) and (Xc), which respectively correspond to the compounds of formula (X) in which R 2 represents a group -CO-NR 16 R 17 and -CO-NR 15 -NR 16 R 17 , where R 15 , R 16 and R 17 are as defined above.
Figure imgb0017

Selon le schéma 6, les composés de formule (XII) peuvent être préparés à partir des composés de formule (XI) par réaction avec du phosgène, du triphosgène ou du trichlorométhyle chloroformate dans le dichlorométhane ou le toluène en présence de triéthylamine ou de pyridine et une amine à des températures variant de -10°C et 80°C. La réaction des composés de formule (XII) avec une amine de formule HN(R16)(R17) ou une hydrazine de formule HN(R15)(NR16R17) aboutit respectivement aux composés de formules (Xb) et (Xc).According to Scheme 6, the compounds of formula (XII) may be prepared from compounds of formula (XI) by reaction with phosgene, triphosgene or trichloromethyl chloroformate in dichloromethane or toluene in the presence of triethylamine or pyridine and an amine at temperatures ranging from -10 ° C to 80 ° C. The reaction of the compounds of formula (XII) with an amine of formula HN (R 16 ) (R 17 ) or a hydrazine of formula HN (R 15 ) (NR 16 R 17 ) results respectively in the compounds of formulas (Xb) and ( xc).

Le schéma 7 présente une voie de préparation des composés de formule (Xd), correspondant aux composés de formule (X) dans lesquels R2 représente un groupe -(CH2)x-NR16R17, où x = 2, 3 ou 4 et où R16 et R17 sont tels que définis ci-avant.

Figure imgb0018
Scheme 7 shows a route of preparation of the compounds of formula (Xd), corresponding to the compounds of formula (X) in which R 2 represents a group - (CH 2 ) x -NR 16 R 17 , where x = 2, 3 or 4 and wherein R 16 and R 17 are as defined above.
Figure imgb0018

Selon le schéma 7, les composés de formule (XIII) peuvent être obtenus par amination réductrice réalisée sur les composés de formule (XI) en présence d'un aldéhyde de formule Q-CO-(CH2)x-2-CHO, où Q représente un groupe -O-alkyle ou -N(O-alkyle)(alkyle), en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1.According to Scheme 7, the compounds of formula (XIII) can be obtained by reductive amination carried out on the compounds of formula (XI) in the presence of an aldehyde of formula Q-CO- (CH 2 ) x-2 -CHO, where Q is -O-alkyl or -N (O-alkyl) (alkyl), using a reductant as described above in connection with Scheme 1.

Puis les composés de formule générale (XIII) peuvent être réduits pour conduire aux aldéhydes de formule (XIV), en utilisant un réducteur tel que l'hydrure de diisobutyl aluminium ou le tétraaluminohydrure de sodium dans le cas où Q est un groupe -O-alkyle, ou par réduction avec l'hydrure de lithium aluminium dans le cas où Q est un groupe -N(O-alkyle)(alkyle) (par exemple -N(OMe)Me), obtenu par exemple par réaction d'un organomagnésien, tel que le chlorure de diisopropylmagnésien, sur les composés de formule (XIII) où Q = -O-alkyle en présence d'une alkylhydroxylalkyle amine telle que la N,O-diméthylhydroxylamine, dans des solvants tels que le tétrahydrofurane ou le diéthyléther à des températures variant de -78°C à 20°C.Then the compounds of general formula (XIII) can be reduced to yield aldehydes of formula (XIV), using a reducing agent such as diisobutyl aluminum hydride or sodium tetraaluminohydride in the case where Q is a group -O- alkyl, or by reduction with lithium aluminum hydride in the case where Q is a group -N (O-alkyl) (alkyl) (for example -N (OMe) Me), obtained for example by reaction of an organomagnesium , such as diisopropylmagnesium chloride, on the compounds of formula (XIII) where Q = -O-alkyl in the presence of an alkylhydroxylalkyl amine such as N, O-dimethylhydroxylamine, in solvents such as tetrahydrofuran or diethyl ether. temperatures ranging from -78 ° C to 20 ° C.

Les composés de formule (Xd) peuvent ensuite être préparés par amination réductrice réalisée en présence d'une amine de formule R17R16NH, en utilisant un réducteur tel que décrit ci-dessus.The compounds of formula (Xd) may then be prepared by reductive amination carried out in the presence of an amine of formula R 17 R 16 NH, using a reducing agent as described above.

Le schéma 8 présente une voie de préparation des composés de formule (Xe), correspondant aux composés de formule (X) dans lesquels R2 représente un groupe -(CH2)x-aryle (où x = 0, 1, 2, 3 ou 4) ou -(CH2)x-hétéroaryle (où x = 1, 2, 3 ou 4).

Figure imgb0019
Scheme 8 shows a route of preparation of the compounds of formula (Xe), corresponding to the compounds of formula (X) in which R 2 represents a group - (CH 2) x -aryl (where x = 0, 1, 2, 3 or 4) or - (CH 2 ) x -heteroaryl (where x = 1, 2, 3 or 4).
Figure imgb0019

Selon le schéma 8, les composés de formules (Xe) dans lesquels R2 représente un groupe -(CH2)x-hétéroaryle (où x = 1, 2 ou 3) peuvent être obtenus par amination réductrice à partir des composés de formule (XI)i, réalisée en présence d'un aldéhyde de formule : hétéroaryle-(CH2)x-1-CHO, en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1.According to Scheme 8, the compounds of formulas (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group (where x = 1, 2 or 3) can be obtained by reductive amination from the compounds of formula ( XI) i, carried out in the presence of an aldehyde of formula: heteroaryl- (CH 2 ) x-1 -CHO, using a reducing agent as described above with reference to Scheme 1.

La même réaction peut également être utilisée pour obtenir les composés de formule (Xd), et ce en utilisant un aldéhyde de formule R17R16N-(CH2)x-1-CHO.The same reaction can also be used to obtain the compounds of formula (Xd), using an aldehyde of formula R 17 R 16 N- (CH 2) x-1 -CHO.

Les composés de formules (XI)ii dans lesquels R2 représente un groupe -(CH2)x-aryle (où x = 0, 1, 2 ou 3) peuvent être obtenus par amination réductrice à partir de la nortropanone protégée sur la fonction amine (telle que la Boc-nortropanone), réalisée en présence d'une amine de formule : aryle-(CH2)x-NH2, en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1. Les composés de formules (Xe) dans lesquels R2 représente un groupe -(CH2)x-aryle peuvent ensuite être obtenus par amination réductrice à partir des composés de formule (XI)ii, réalisée en présence d'un dérivé de groupe R1 de type oxo.The compounds of formulas (XI) ii in which R 2 represents a group - (CH 2) x -aryl (where x = 0, 1, 2 or 3) can be obtained by reductive amination from nortropanone protected on the amine function (such as Boc-nortropanone), carried out in the presence of an amine of formula: aryl- (CH 2 ) x -NH 2 , using a reducing agent as described above in connection with Scheme 1. The compounds of formulas ( Xe) in which R 2 represents a - (CH 2 ) x -aryl group can then be obtained by reductive amination from the compounds of formula (XI) ii, carried out in the presence of an oxo-type derivative of R 1 group.

Le schéma 9 détaille une alternative pour la synthèse des composés de formule (Xe) dans lesquels R2 représente un groupe -(CH2)x-hétéroaryle, où x est égal à 2 ou 3.

Figure imgb0020
Scheme 9 details an alternative for the synthesis of compounds of formula (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group, where x is 2 or 3.
Figure imgb0020

Selon le schéma 9, les composés de formule (XIII), dans lesquels Q représente un groupe -O-alkyle, peuvent être réduits en alcools correspondants en utilisant un réducteur tel que l'hydrure de lithium aluminium dans un solvant tel que le diéthyléther ou le tétrahydrofurane, à des températures variant de -60°C à 20°C.According to Scheme 9, the compounds of formula (XIII), in which Q represents a -O-alkyl group, can be reduced to the corresponding alcohols by using a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran, at temperatures ranging from -60 ° C to 20 ° C.

Le groupement hydroxyle des composés de formule (XV) est ensuite transformé en groupement partant (Lg), tels que le chlorure ou le mésylate, par exemple par action de tétrabromométhane et de triphénylphosphine dans un solvant tel que le dichlorométhane ou par action de chlorure de méthanesulfonyle en présence d'une base organique telle que la triéthylamine à des températures variant de -20°C à la température ambiante, pour conduire aux composés de formule (XVI).The hydroxyl group of the compounds of formula (XV) is then converted into a leaving group (Lg), such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of sodium chloride. methanesulfonyl in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C to room temperature, to yield compounds of formula (XVI).

Les composés de formule (Xe) sont ensuite synthétisés par une réaction de substitution nucléophile entre les composés de formule (XVI) et l'anion d'un hétéroaryle (groupe « Het »).The compounds of formula (Xe) are then synthesized by a nucleophilic substitution reaction between the compounds of formula (XVI) and the anion of a heteroaryl ("Het" group).

Le schéma 10 présente une voie de préparation des composés de formule (I), dans lesquels R4 représente un groupe de formule (d) tel que défini précédemment, où r = 1, 2 ou 3, s = 1 et U représente un atome d'azote.

Figure imgb0021
Scheme 10 shows a route of preparation of the compounds of formula (I), in which R 4 represents a group of formula (d) as defined above, where r = 1, 2 or 3, s = 1 and U represents an atom nitrogen.
Figure imgb0021

Les composés de formule (XXII) peuvent être obtenus par alkylation des composés de formule (IV) [où R5 = H] par des tétrahydroisoquinolines de formule (XX), en substituant le groupe partant (Lg) des composés de formule (XX) par l'anion des composés de formule (IV), formé par réaction avec l'hydrure de sodium dans un solvant tel que le diméthylformamide à des températures variant de -20°C à 60°C, ou par réaction avec le diisopropylamidure de lithium dans un solvant tel que le tétrahydrofurane ou le diéthyléther à des températures variant de -78°C à 25°C.The compounds of formula (XXII) can be obtained by alkylation of the compounds of formula (IV) [where R 5 = H] by tetrahydroisoquinolines of formula (XX), substituting the leaving group (Lg) of the compounds of formula (XX) by the anion of the compounds of formula (IV), formed by reaction with sodium hydride in a solvent such as dimethylformamide at temperatures ranging from -20 ° C to 60 ° C, or by reaction with lithium diisopropylamide in a solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from -78 ° C to 25 ° C.

Les composés de formule (XX) sont préparés dans des conditions classiques, comme par transformation du groupement hydroxyle des composés de formule (XXI) en groupe partant, tels que le chlorure ou le mésylate, par exemple par action de tétrabromométhane et de triphénylphosphine dans un solvant tel que le dichlorométhane ou par action de chlorure de méthanesulfonyle en présence d'une base organique telle que la triéthylamine à des températures variant de -20°C à la température ambiante. Les composés de formule (XXI) sont synthétisés selon les méthodes d'alkylation connues de l'Homme de l'art de la 1,2,3,4-tétrahydroisoquinoline commerciale.The compounds of formula (XX) are prepared under standard conditions, such as by conversion of the hydroxyl group of compounds of formula (XXI) into a leaving group, such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of methanesulfonyl chloride in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C to room temperature. The compounds of formula (XXI) are synthesized according to the alkylation methods known to those skilled in the art of commercial 1,2,3,4-tetrahydroisoquinoline.

La fonction amine des composés de formule (XII) est déprotégée, dans des conditions telles que décrites dans le schéma 1, pour aboutir aux composés de formule (I) [où R5 = H et R4 = 2-alkyl-1,2,3,4-tétrahydroisoquinoline].The amine function of the compounds of formula (XII) is deprotected, under conditions as described in scheme 1, to yield compounds of formula (I) [where R 5 = H and R 4 = 2-alkyl-1,2,3,4-tetrahydroisoquinoline].

Selon une variante du schéma 1, dans le cas où les composés de formule (I) comprennent, en tant que groupe R4, un groupe de formule (a) de type cyclohexyle, c'est-à-dire un groupe de formule (a) où a = 0, p = 2 et X = -C(R6)(R7)-, où R6 représente un groupe -OR8, R7 et R8 étant tels que définis ci-avant, alors la préparation des composés de formule (I) peut être réalisée comme décrit dans le schéma 11.

Figure imgb0022
According to a variant of Scheme 1, in the case where the compounds of formula (I) comprise, as R 4 group, a group of formula (a) of cyclohexyl type, that is to say a group of formula ( a) where a = 0, p = 2 and X = -C (R 6 ) (R 7 ) -, where R 6 represents a group -OR 8 , R 7 and R 8 being as defined above, then the Preparation of the compounds of formula (I) can be carried out as described in scheme 11.
Figure imgb0022

Selon le schéma 11, les composés de formule (XVIII) peuvent être obtenus par une amination réductrice entre le composé de formule (XVII) commercial et les composés de formule (V), dans des conditions telles que décrites dans le schéma 1.According to Scheme 11, the compounds of formula (XVIII) can be obtained by reductive amination between the compound of formula (XVII) and the commercial compounds of formula (V) under conditions as described in Scheme 1.

La déprotection de la fonction oxo du composé de formule (XVIII) en présence d'un acide tel que l'acide chlorhydrique ou le pyridinium tosylate dans le tétrahydrofurane ou l'acétone à des températures comprises entre 0°C et 80°C conduit au composé de formule (XIX).Deprotection of the oxo function of the compound of formula (XVIII) in the presence of an acid such as hydrochloric acid or pyridinium tosylate in tetrahydrofuran or acetone at temperatures between 0 ° C. and 80 ° C. compound of formula (XIX).

Les composés de formule (If) sont préparés par réduction des composés de formule (XIX) dans des conditions telles que décrites dans le schéma 6.The compounds of formula (If) are prepared by reducing the compounds of formula (XIX) under conditions as described in scheme 6.

Quand R8 est différent d'un atome d'hydrogène, on réalise une fonctionnalisation des composés de formule (If), par exemple une alkylation en présence d'une base telle que l'hydrure de sodium et d'un dérivé du groupe R8 comportant un groupement partant Lg, ce qui aboutit aux composés de formule (lg).When R 8 is different from a hydrogen atom, functionalization of the compounds of formula (If) is carried out, for example alkylation in the presence of a base such as sodium hydride and a group R derivative. 8 having a leaving group Lg, which results in the compounds of formula (lg).

Dans les schémas 1 à 11, les composés de départ et les réactifs, quand leur mode de préparation n'est pas décrit, sont disponibles dans le commerce ou décrits dans la littérature, ou bien peuvent être préparés selon des méthodes qui y sont décrites ou qui sont connues de l'Homme de l'art.In Schemes 1 to 11, the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art.

L'invention, selon un autre de ses aspects, a également pour objet les composés de formules (II), (IV), (V), (Vl), (VIII), (IX), (X), (XVIII) et (XIX) : ces composés sont utiles comme intermédiaires de synthèse des composés de formule (I).The invention, according to another of its aspects, also relates to the compounds of formulas (II), (IV), (V), (VI), (VIII), (IX), (X), (XVIII) and (XIX): these compounds are useful as synthesis intermediates for the compounds of formula (I).

Les exemples suivants décrivent la préparation de certains composés conformes à l'invention. Ces exemples ne sont pas limitatifs et ne font qu'illustrer la présente invention. Les numéros des composés exemplifiés renvoient à ceux donnés dans le tableau ci-après, qui illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

Exemple 1: N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo [3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea (composé n° 1) Example 1: N - [8- (4-Chloro- N -piperidin-4-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea (compound no. 1) 1.1 : tert-butyl 3-(cyclohexylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate1.1: tert-butyl 3- (cyclohexylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate

On dissout 9,1 g de cyclohexylamine et 10,3 g de Boc-nortropinone dans 150mL d'éthanol. On additionne à température ambiante 14,3 g de tétraisopropoxyde de titane. Le milieu réactionnel est agité pendant 16h. On additionne par fractions 2,6 g de borohydrure de sodium à 0°C, et le milieu réactionnel est alors agité à température ambiante durant 2 heures. Après addition de 50 ml d'eau et de 20 ml d'ammoniaque aqueux (28% dans l'eau), le précipité blanc formé dans le milieu réactionnel est filtré sur un lit de célite. Le solide est lavé plusieurs fois par le dichlorométhane. Les phases organiques sont ensuite rassemblées, lavées à l'eau, séchées sur MgSO4 et concentrées. Le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 10%. On obtient 7,7g du composé endo tert-butyl 3-(cyclohexylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate et 1,2 g du composé exo tert-butyl 3-(cyclohexylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate. La suite de la synthèse concerne le composé endo.9.1 g of cyclohexylamine and 10.3 g of Boc-nortropinone are dissolved in 150 ml of ethanol. 14.3 g of titanium tetraisopropoxide are added at room temperature. The reaction medium is stirred for 16 hours. 2.6 g of sodium borohydride are added in portions at 0 ° C., and the reaction medium is then stirred at ambient temperature for 2 hours. After addition of 50 ml of water and 20 ml of aqueous ammonia (28% in water), the white precipitate formed in the reaction medium is filtered on a bed of celite. The solid is washed several times with dichloromethane. The organic phases are then combined, washed with water, dried over MgSO 4 and concentrated. The crude product obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 10%. 7.7 g of the endo tert-butyl 3- (cyclohexylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate compound and 1.2 g of the exo tert-butyl 3- (cyclohexylamino) -8-azabicyclo compound are obtained. [3.2.1] octane-8-carboxylate. The rest of the synthesis concerns the endo compound.

1.2: tert-butyl 3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1] octane-8-carboxylate1.2: tert-butyl 3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate

On place 0,64 mL de diphosgène dans 10 mL de dichlorométhane à 0°C sous N2. Une solution de 1,0 g de composé endo tert-butyl 3-(cyclohexylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate et de 2,26 mL de triéthylamine dans 10 mL de dichlorométhane est ajoutée goutte à goutte. La solution est agitée 30 min à 0°C puis 4h à température ambiante. On ajoute alors 5 mL de triéthylamine et 1,0 mL de diphosgène. Après agitation pendant 2h à température ambiante, 1,68 mL de diéthylamine sont ajoutés. Le mélange est agité à température ambiante pendant 16h. Après concentration, on ajoute de l'acide chlorhydrique 0,5N jusqu'à pH acide. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4, et concentration à sec, le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange 99/1 puis 95/5 de dichlorométhane et de méthanol pour conduire à 1,60 g de tert-butyl 3-{cyclohexyl[(diethylamino) carbonyl]amino}-8-azabicyclo[3.2.1] octane-8-carboxylate en mélange avec de la diéthylurée.0.64 ml of diphosgene are placed in 10 ml of dichloromethane at 0 ° C. under N 2 . A solution of 1.0 g of endo- tert-butyl 3- (cyclohexylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate compound and 2.26 ml of triethylamine in 10 ml of dichloromethane is added dropwise. . The solution is stirred for 30 min at 0 ° C. and then 4 h at room temperature. 5 mL of triethylamine and 1.0 mL of diphosgene are then added. After stirring for 2h at room temperature, 1.68 mL of diethylamine is added. The mixture is stirred at ambient temperature for 16 hours. After concentration, 0.5N hydrochloric acid is added until the pH is acidic. It is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the residue obtained is chromatographed on silica gel eluting with a 99/1 and then 95/5 mixture of dichloromethane and methanol to yield 1.60 g of tert - butyl. {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate mixed with diethylurea.

1.3 : N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N',N'-diethylurea1.3: N- 8-azabicyclo [3.2.1] oct-3-yl- N- cyclohexyl- N ', N ' -diethylurea

On place 3,0 g de tert-butyl 3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate en mélange avec la diéthylurée dans 37 mL d'acide chlorhydrique 2N-dans le diéthyléther. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on reprend avec une solution aqueuse d'acide chlorhydrique 1 N. On extrait à l'acétate d'éthyle puis on ajoute une solution aqueuse de soude 1N jusqu'à pH 10. On extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4, et concentration à sec, on obtient 1,8 g de N-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea.3.0 g of tert - butyl 3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate are placed in admixture with the diethylurea in 37 ml of 2N hydrochloric acid. in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, the reaction mixture is taken up in 1N aqueous hydrochloric acid solution. The mixture is extracted with ethyl acetate and then an aqueous 1N sodium hydroxide solution is added until pH 10 is obtained. ethyl until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 1.8 g of N- 8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ' , N' -diethylurea are obtained.

1.4: tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl] amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate1.4: tert-butyl [(1 R ) -1- (4-chlorobenzyl) -2- (3 - {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8-yl) 2-oxoethyl] carbamate

On solubilise 1,8 g de N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N',N'-diethylurea dans 70 mL de dichlorométhane en présence de 1,75 g de Boc-D-4-chlorophénylalanine, de 0,79 g d'hydroxybenzotriazole, de 1,12 g de chlorhydrate de 1-(3-diméthylaminopropyl)-3-éthyl-carbodiimide et de 1,02 mL de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après évaporation à sec, le résidu est hydrolysé et extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié sur gel de silice en éluant avec un mélange 99/1 de dichlorométhane et de méthanol pour conduire à 1,42 g de tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate.1.8 g of N- 8-azabicyclo [3.2.1] oct-3-yl- N- cyclohexyl- N ', N ' -diethylurea are solubilized in 70 ml of dichloromethane in the presence of 1.75 g of Boc-D. 4-chlorophenylalanine, 0.79 g of hydroxybenzotriazole, 1.12 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 1.02 mL of diisopropylethylamine. The mixture is stirred 16h at room temperature. After evaporation to dryness, the residue is hydrolysed and extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed on silica gel eluting with a 99/1 mixture of dichloromethane and methanol to yield 1.42 g of tert - butyl [(1 R ) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] carbamate.

1.5 : N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea1.5: N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea

On place 1,42 g de tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl [(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate dans 12 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité pendant 3h à température ambiante. On rajoute 5 mL d'acide chlorhydrique 2N dans le diéthyléther et l'agitation est maintenue 16h. Après évaporation à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 95/5/0,5 de dichlorométhane, de méthanol et d'ammoniaque aqueuse. On obtient 1,03 g de N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1 ]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea.Was placed 1.42 g of tert -butyl [(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct- 8-yl) -2-oxoethyl] carbamate in 12 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred for 3h at room temperature. 5 ml of 2N hydrochloric acid are added to the diethyl ether and stirring is maintained for 16 hours. After evaporation to dryness, the crude obtained is chromatographed on silica gel, eluting with a 95/5 / 0.5 mixture of dichloromethane, methanol and aqueous ammonia. 1.03 g of N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea are obtained.

1.6 : tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl] amino}-8-azabicyc)o[3.2.1]oct-8-yl)-2-oxoethyl]amino}piperidine-1-carboxylate1.6: tert-butyl 4 - {[(1 R ) -1- (4-chlorobenzyl) -2- (3 - {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct- 8-yl) -2--oxoethyl] amino} piperidine-1-carboxylate

On solubilise 0,41 g de N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea dans 4 mL de dichlorométhane sous N2 en présence de 0,17 g de N-BOC-pipéridone et de 0,23 g de triacétoxyborohydrure de sodium et on agite pendant 16h à température ambiante. Après évaporation et hydrolyse, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. On sèche sur MgSO4 et on concentre à sec. Le brut est chromatographié sur gel de silice en éluant avec mélange 98/2 de dichlorométhane et de méthanol. On obtient alors 0,37 g de tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}piperidine-1-carboxylate.0.41 g of N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ' , N' -diethylurea are solubilized in 4 parts by volume. mL of N 2 dichloromethane in the presence of 0.17 g of N- BOC-piperidone and 0.23 g of sodium triacetoxyborohydride and stirred for 16 h at room temperature. After evaporation and hydrolysis, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. It is dried over MgSO 4 and concentrated to dryness. The crude is chromatographed on silica gel eluting with 98/2 mixture of dichloromethane and methanol. Is then obtained 0.37 g of tert-butyl 4 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2. 1] oct-8-yl) -2-oxoethyl] amino} piperidine-1-carboxylate.

1.7: chlorhydrate de N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo [3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea1.7: N - [8- (4-chloro- N -piperidin-4-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ' , N hydrochloride ' -diethylurea

On solubilise 0,37 g de tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}piperidine-1-carboxylate dans 2,74 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, le brut est chromatographié sur gel de silice en éluant avec un mélange 95/5/0,5 de dichlorométhane, de méthanol et d'ammoniaque aqueuse. On obtient alors 0,27 g de chlorhydrate de N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N-diethylurea.
Point de fusion > 210°C, M+H+ = 572, [α]D 20 = -2,0 (c=1,002g/100 mL, MeOH).Is dissolved 0.37 g of tert -butyl 4 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1 ] oct-8-yl) -2-oxoethyl] amino} piperidine-1-carboxylate in 2.74 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, the crude is chromatographed on silica gel, eluting with a 95/5 / 0.5 mixture of dichloromethane, methanol and aqueous ammonia. 0.27 g of N - [8- (4-chloro- N -piperidin-4-yl-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N -hydrochloride are then obtained. cyclohexyl- N ' , N- diethylurea.
Melting point> 210 ° C., M + H + = 572, [α] D 20 = -2.0 (c = 1.002 g / 100 mL, MeOH).

Exemple 2 : N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea (composé n° 4) Example 2 : N - {8- [4-chloro- N - (tetrahydro-2 H -pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ' , N' -diethylurea (compound No. 4) 2.1 : N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo [3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea2.1: N - {8- [4-chloro- N - (tetrahydro-2 H -pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl - N ', N ' -diethylurea

On solubilise 0,30 g du composé endo N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea obtenu lors de l'étape 1.5 dans 3 mL de dichlorométhane sous N2 en présence de 0,061 g de tétrahydro-4H-pyran-4-one et de 0,17 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 3 jours à température ambiante. Après évaporation et hydrolyse avec une solution aqueuse saturée d'hydrogénocarbonate de sodium, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. On sèche sur MgSO4 et on concentre à sec. Le brut est chromatographié sur gel de silice en éluant avec un mélange 99/1 puis 98/2 de dichlorométhane et de méthanol. On obtient alors 0,23 g de N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea.0.30 g of the compound endo N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea is solubilized. obtained in step 1.5 in 3 ml of dichloromethane under N2 in the presence of 0.061 g of tetrahydro-4 -pyran-4-one H and 0.17 g of sodium triacetoxyborohydride. The reaction medium is stirred for 3 days at room temperature. After evaporation and hydrolysis with a saturated aqueous solution of sodium hydrogencarbonate, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. It is dried over MgSO 4 and concentrated to dryness. The crude is chromatographed on silica gel, eluting with a 99/1 and then 98/2 mixture of dichloromethane and methanol. Then we obtain 0.23 g of N - {8- [4-chloro-N- (tetrahydro-2 H- pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3- N -cyclohexyl- N ' , N' -diethylurea.

2.2 : Chlorhydrate de N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N,N'-diethylurea2.2: N - {8- [4-chloro- N - (tetrahydro-2 H- pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} - N -cyclohexyl- N , N ' -diethylurea

On solubilise 0,23 g de N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea dans 5 mL de diéthyléther puis on ajoute 0,20 mL d'acide chlorhydrique 2N dans le diéthyléther. On triture, on rince avec du diéthyléther et on essore le précipité obtenu. Les cristaux sont ensuite séchés sur P2O5 sous pression réduite. On obtient 0,19 g de N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phehylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea.
Point de fusion > 210°C, M+H+ = 573, [α]D 20 = -5,9 (c=0,553g/100 mL, DMSO). RMN 1H (200MHz, DMSO-d + D2O) : 7,31 (d, J=8 Hz, 2H), 7,19 (d, J=8 Hz, 2H), 4,62 (m, 1 H), 4,41 (m, 1 H), 3,90 (m, 3H) 3,25 (m, 5H), 2,88 (m, 5H), 2,10-1,05 (m, 23H), 0,91 (t, J=4Hz, 6H). Analyse élémentaire : exp %C= 61,46, %H : 8,10, %N : 8,88 ; th : %61,50, %H : 8,34 ,%N : 8,960.23 g of N - {8- [4-chloro- N - (tetrahydro-2 H -pyran-4-yl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl are solubilized. } - N -cyclohexyl- N ' , N' -diethylurea in 5 mL of diethyl ether and then 0.20 mL of 2N hydrochloric acid in diethyl ether. Triturated, rinsed with diethyl ether and the precipitate obtained is filtered off. The crystals are then dried over P 2 O 5 under reduced pressure. 0.19 g of N - {8- [4-chloro- N- (tetrahydro- 2H- pyran-4-yl) -D-phehylalanyl] -8-azabicyclo [3.2.1] oct-3-yl are obtained. N -cyclohexyl- N ' , N' -diethylurea.
Melting point> 210 ° C., M + H + = 573, [α] D 20 = -5.9 (c = 0.553 g / 100 mL, DMSO). 1 H NMR (200MHz, DMSO-d + D 2 O): 7.31 (d, J = 8Hz, 2H), 7.19 (d, J = 8Hz, 2H), 4.62 (m, 1 H), 4.41 (m, 1H), 3.90 (m, 3H) 3.25 (m, 5H), 2.88 (m, 5H), 2.10-1.05 (m, 23H). ), 0.91 (t, J = 4Hz, 6H). Elemental analysis: Exp. C = 61.46,% H: 8.10,% N: 8.88; th:% 61.50,% H: 8.34,% N: 8.96

Exemple 3 : N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea (composé n° 5) Example 3 : N - [8- ( N- 8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N - cyclohexyl- N ', N' -diethylurea (compound No. 5) 3.1 : tert-butyl 3-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl] amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate3.1: tert-butyl 3 - {[(1 R ) -1- (4-chlorobenzyl) -2- (3 - {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8- yl) -2-oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8 carboxylate

On solubilise 0,24 g du composé endo N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea obtenu lors de l'étape 1.5 dans 5 mL de dichlorométhane sous N2 en présence de 0,169 g de Boc-nortropanone et de 0,26 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. On ajoute 0,085 g de Boc-nortropinone et 2,6g de triacétoxyborohydrure de sodium et l'agitation est maintenue 2 jours. Après évaporation à sec, on ajoute 1 mL de méthanol et 4 g de résine DOWEX® 50X2. On agite pendant 1h30. Après filtration et lavage de la résine par du tétrahydrofurane et du méthanol, on relargue le composé attendu en ajoutant une solution 1 N d'ammoniaque dans le méthanol. Le méthanol est évaporé pour conduire à 0,21 g de endo et exo tert-butyl 3-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate. La suite de la synthèse se fait sur ce mélange.0.24 g of the compound endo N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ' , N' -diethylurea is solubilized. obtained in step 1.5 in 5 ml of dichloromethane under N 2 in the presence of 0.169 g of Boc-nortropanone and 0.26 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. 0.085 g of Boc-nortropinone and 2.6 g of sodium triacetoxyborohydride are added and stirring is maintained for 2 days. After evaporation to dryness, was added 1 mL of methanol and 4 g of Dowex ® 50X2 resin. It is stirred for 1h30. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is recovered by adding a 1N solution of ammonia in methanol. The methanol is evaporated to yield 0.21 g of endo and exo tert-butyl 3 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate. The rest of the synthesis is done on this mixture.

3.2 : Chlorhydrate de N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea3.2: N- [8- ( N- 8-Azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] hydrochloride N -cyclohexyl- N ', N ' -diethylurea

On place 0,21 g de tert-butyl 3-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl [(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate dans 1,53 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité une nuit à température ambiante. On triture, on rince avec du diéthyléther et on essore le précipité obtenu. Les cristaux sont ensuite séchés sur P2O5 sous pression réduite. On obtient 0,12g de chlorhydrate de N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea.
Point de fusion = 155°C; M+H+ = 598.0.21 g of tert -butyl 3 is placed - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1 ] oct-8-yl) -2-oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate in 1.53 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred overnight at room temperature. Triturated, rinsed with diethyl ether and the precipitate obtained is filtered off. The crystals are then dried over P 2 O 5 under reduced pressure. 0.12 g of N - [8- ( N- 8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3 hydrochloride are obtained. N- cyclohexyl- N ', N ' -diethylurea.
Melting point = 155 ° C; M + H + = 598.

Exemple 4 : N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea (composé n°11) Example 4 : N - [8- (4-chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct 3-yl] -N- cyclohexyl- N ', N ' -diethylurea (Compound No. 11) 4.1 : tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine-1-carboxylate4.1: tert-butyl (2 S, 4 R) -4-hydroxy-2 - {[methoxy (methyl) amino] carbonyl} pyrrolidine-1-carboxylate

On dissout 1,85 g de (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline dans 80 mL de dichlorométhane à 0°C sous N2. On ajoute 3,72 mL de triéthylamine et 1,97 mL de chloroformiate de tert-butyle. Le milieu réactionnel est agité pendant 1h à température ambiante. Parallèlement, une solution de diméthylhydroxylamine est préparée par addition de 1,86 mL de triéthylamine à une solution de 1,56 g de chlorhydrate de diméthylhydroxylamine dans le dichlorméthane, puis par filtration du chlorhydrate de triéthylamine. Cette seconde solution est ajoutée doucement à 0°C à la première. Le milieu réactionnel est agité pendant 16h à température ambiante. Après hydrolyse avec une solution aqueuse d'acide chlorhydrique 0,5N, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est séchée sur MgSO4 et concentrée à sec. On obtient 0,9 g de tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl) amino]carbonyl}pyrrolidine-1-carboxylate qui est utilisé tel quel par la suite.1.85 g of (4 R ) -1- ( tert- butoxycarbonyl) -4-hydroxy-L-proline are dissolved in 80 ml of dichloromethane at 0 ° C. under N 2 . 3.72 ml of triethylamine and 1.97 ml of tert- butyl chloroformate are added. The reaction medium is stirred for 1 h at room temperature. In parallel, a solution of dimethylhydroxylamine is prepared by adding 1.86 mL of triethylamine to a solution of 1.56 g of dimethylhydroxylamine hydrochloride in dichloromethane, followed by filtration of triethylamine hydrochloride. This second solution is slowly added at 0 ° C to the first. The reaction medium is stirred for 16 hours at room temperature. After hydrolysis with an aqueous solution of 0.5N hydrochloric acid, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is dried over MgSO 4 and concentrated to dryness. Is obtained 0.9 g of tert -butyl (2 S, 4 R) -4-hydroxy-2 - {[methoxy (methyl) amino] carbonyl} pyrrolidine-1-carboxylate which was used as such subsequently.

4.2 : tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate4.2: tert -butyl (2 S, 4 R) -2-formyl-4-hydroxypyrrolidine-1-carboxylate

On dissout 0,9 g de tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl)amino] carbonyl}pyrrolidine-1-carboxylate dans 31 mL de diéthyléther sous N2. On place le milieu réactionnel à 0°C et on ajoute doucement 3,41 mL d'hydrure d'hydrure de lithium aluminium 1 N dans le tétrahydrofurane. Le mélange est agité pendant 2h à 0°C. Après hydrolyse avec une solution aqueuse de sulfate de potassium, on extrait au diéthyléther jusqu'à épuisement de la phase aqueuse. On sèche sur MgSO4 et on concentre à sec. Le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 9/1 de dichlorométhane et de méthanol. On obtient 0,45g de tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate.0.9 g of tert - butyl (2 S , 4 R ) -4-hydroxy-2 - {[methoxy (methyl) amino] carbonyl} pyrrolidine-1-carboxylate are dissolved in 31 ml of diethyl ether under N 2 . The reaction medium is placed at 0 ° C. and 3.41 ml of 1N lithium aluminum hydride hydride in tetrahydrofuran are slowly added. The mixture is stirred for 2 h at 0 ° C. After hydrolysis with an aqueous solution of potassium sulfate, the mixture is extracted with diethyl ether until the aqueous phase is exhausted. It is dried over MgSO 4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 0.45 g of tert - butyl (2 S , 4 R ) -2-formyl-4-hydroxypyrrolidine-1-carboxylate are obtained.

4.3 : tert-butyl (2S,4R)-2-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino) carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}methyl)-4-hydroxypyrrolidine-1-carboxylate4.3: tert -butyl (2 S, 4 R) -2 - ({[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} methyl) -4-hydroxypyrrolidine-1-carboxylate

On solubilise 0,24 g du composé endo N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea obtenu lors de l'étape 1.5 dans 3 mL de dichlorométhane sous N2 en présence de 0,16 g de tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate et de 0,233 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute 1 mL de méthanol et 4 g de résine DOWEX® 50X2. On agite pendant 1h30. Après filtration et lavage de la résine par du tétrahydrofurane et du méthanol, on relargue le composé attendu en ajoutant une solution 1 N d'ammoniaque dans le méthanol: Le méthanol est évaporé pour conduire à 0,28 g de tert-butyl (2S,4R)-2-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}methyl)-4-hydroxypyrrolidine-1-carboxylate.0.24 g of the compound endo N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea is solubilized. obtained in step 1.5 in 3 ml of dichloromethane under N 2 in the presence of 0.16 g of tert - butyl (2 S , 4 R ) -2-formyl-4-hydroxypyrrolidine-1-carboxylate and 0.233 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, was added 1 mL of methanol and 4 g of Dowex ® 50X2 resin. It is stirred for 1h30. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is salted out by adding a 1N solution of ammonia in methanol: The methanol is evaporated to yield 0.28 g of tert - butyl (2 S). , 4 R ) -2 - ({[(1 R ) -1- (4-chlorobenzyl) -2- (3 - {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8 -yl) -2-oxoethyl] amino} methyl) -4-hydroxypyrrolidine-1-carboxylate.

4.4: N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea4.4: N - [8- (4-chloro- N - {[( 2S , 4R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct- 3-yl] - N -cyclohexyl- N ', N ' -diethylurea

On solubilise 0,28 g de tert-butyl (2S,4R)-2-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}methyl)-4-hydroxypyrrolidine-1-carboxylate dans 5 mL de diéthyléther puis on ajoute 2,7 mL d'acide chlorhydrique 2N dans le diéthyléther. On triture, on rince avec du diéthyléther et on essore le précipité obtenu qui est chromatographié sur gel de silice en éluant avec un mélange 90/10/1 de dichlorométhane, de méthanol et d'ammoniaque aqueuse.. On obtient 0,18 g de N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea.Is dissolved 0.28 g of tert -butyl (2 S, 4 R) -2 - ({[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino } -8-azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} methyl) -4-hydroxypyrrolidine-1-carboxylate in 5 mL of diethyl ether and 2.7 mL of 2N hydrochloric acid are then added in diethyl ether. It is triturated, rinsed with diethyl ether and the precipitate obtained is filtered off and chromatographed on silica gel, eluting with a 90/10/1 mixture of dichloromethane, methanol and aqueous ammonia. 0.18 g of N - [8- (4-chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3 N -cyclohexyl- N ', N ' -diethylurea.

4.5 : Chlorhydrate de N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea4.5: N - [8- (4-chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2.1] hydrochloride oct-3-yl] - N -cyclohexyl- N ' , N' -diethylurea

On place 0,18 g de N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea dans 0,4 mL d'acide chlorhydrique 2N dans le diéthyléther. On triture, on rince avec du diéthyléther et on essore le précipité obtenu. On obtient 0,16 g de chlorhydrate de N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea.
Point de fusion > 200°C, M+H+ = 588 , [α]D 20 = -10,7° (c=0,646 g/100 mL, DMSO).0.18 g of N - [8- (4-chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo [3.2] are placed .1] oct-3-yl] - N- cyclohexyl- N ', N' -diethylurea in 0.4 mL of 2N hydrochloric acid in diethyl ether. Triturated, rinsed with diethyl ether and the precipitate obtained is filtered off. 0.16 g of N - [8- (4-chloro- N - {[(2 S , 4 R ) -4-hydroxypyrrolidin-2-yl] methyl} -D-phenylalanyl) -8-azabicyclo hydrochloride are obtained. [3.2.1] oct-3-yl] - N- cyclohexyl- N ', N' -diethylurea.
Melting point> 200 ° C, M + H + = 588, [α] D 20 = -10.7 ° (c = 0.646 g / 100 mL, DMSO).

Exemple 5 : N-{8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo [3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea (composé n° 18) Example 5 : N - {8- [ N - (2-aminoethyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' -diethylurea (compound no. 18) 5.1 : tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino) carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl)carbamate5.1: tert-butyl (2 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2.1] oct-8 -yl) -2-oxoethyl] amino} ethyl) carbamate

On solubilise 0,24 g du composé endo N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea obtenu lors de l'étape 1.5 dans 5 mL de dichlorométhane sous N2 en présence de 0,10 g de tert-butyl N-(2-oxoethyl)carbamate et de 0,22 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute 0,05 g de tert-butyl N-(2-oxoethyl)carbamate et 0,1g de triacétoxyborohydrure de sodium et on maintient l'agitation pendant 3 jours. Après addition de 1 mL de méthanol et 4 g de résine DOWEX® 50X2, on agite pendant 1h30. Après filtration et lavage de la résine par du tétrahydrofurane et du méthanol, on relargue le composé attendu en ajoutant une solution 1 N d'ammoniaque dans le méthanol. Le méthanol est évaporé pour conduire à 0,14 g de tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl [(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl) carbamate.0.24 g of the compound endo N - [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea is solubilized. obtained in step 1.5 in 5 ml of dichloromethane under N 2 in the presence of 0.10 g of tert -butyl N- (2-oxoethyl) carbamate and 0.22 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, 0.05 g of tert -butyl N- (2-oxoethyl) carbamate and 0.1 g of sodium triacetoxyborohydride are added and the stirring is maintained for 3 days. After addition of 1 ml of methanol and 4 g of DOWEX ® 50X2, stirred for 1h30. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is recovered by adding a 1N solution of ammonia in methanol. The methanol is evaporated to yield 0.14 g of tert -butyl (2 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8 azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} ethyl) carbamate.

5.2 : N-{8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea5.2: N - {8- [ N - (2-aminoethyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N ' - diethylurea

On place 0,14 g de tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl [(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl)carbamate dans 1,1 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité 1h à température ambiante. On triture, on rince avec du diéthyléther et on essore le précipité obtenu. Le sel ainsi obtenu est chromatographié sur gel de silice en éluant avec un mélange 98/2/0,2 puis 95/5/0,5 de dichlorométhane, de méthanol et d'ammoniaque aqueuse. On obtient 0,05g de chlorhydrate de N-{8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea.
Point de fusion = 105°C, M+H+ = 532, [α]D 20 = -12,6°(c=0,521 g/100 mL, DMSO).Was placed 0.14 g of tert -butyl (2 - {[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2. 1] oct-8-yl) -2-oxoethyl] amino} ethyl) carbamate in 1.1 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred for 1 hour at room temperature. Triturated, rinsed with diethyl ether and the precipitate obtained is filtered off. The salt thus obtained is chromatographed on silica gel, eluting with a 98/2 / 0.2 and then 95/5 / 0.5 mixture of dichloromethane, methanol and aqueous ammonia. 0.05 g of N - {8- [ N - (2-aminoethyl) -4-chloro-D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl) hydrochloride are obtained. N ', N ' -diethylurea.
Melting point = 105 ° C, M + H + = 532, [α] D 20 = -12.6 ° (c = 0.521 g / 100 mL, DMSO).

Exemple 6 : N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea (composé n° 22) Example 6: N - (8- {4-chloro- N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct -3-yl) - N -cyclohexyl- N ' , N' -diethylurea (Compound No. 22) 6.1 : tert-butyl (3R)-3-{[methoxy(methyl)amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate6.1: tert -butyl (3 R) -3 - {[methoxy (methyl) amino] carbonyl} -3,4-dihydroisoquinoline-2 (1H) -carboxylate

On dissout 6,95 g de Boc-D-Tic-OH dans 25 mL de dichlorométhane. On ajoute 2,69 g de chloryhydrate de diméthylhydroxylamine et 11,68 g de bromo-tris-pyrrolidino-phosphonium hexafluorophosphate. Après refroidissement de la solution à 0°C, on additionne lentement 9,72 mL de diisopropylamine. Puis le milieu réactionnel est agité à température ambiante pendant .16h. Après hydrolyse, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. On sèche sur MgSO4 et on concentre à sec. Le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 99/1 de dichlorométhane et de méthanol. On obtient 7,4 g de tert-butyl (3R)-3-{[methoxy(methyl)amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate.6.95 g of Boc-D-Tic-OH are dissolved in 25 ml of dichloromethane. 2.69 g of dimethylhydroxylamine hydrochloride and 11.68 g of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate are added. After cooling the solution to 0 ° C., 9.72 ml of diisopropylamine are slowly added. The reaction medium is then stirred at ambient temperature for 16 h. After hydrolysis, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. It is dried over MgSO 4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 7.4 g of tert - butyl (3R) -3 - {[methoxy (methyl) amino] carbonyl} -3,4-dihydroisoquinolin-2 ( 1H ) -carboxylate are obtained.

6.2 : tert-butyl (3R)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate6.2: tert -butyl (3 R) -3-formyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

On dissout 7,4g de tert-butyl (3R)-3-{[methoxy(methyl)amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate dans 31 mL de diéthyléther sous N2. On place le milieu réactionnel à 0°C et on ajoute doucement 0,98 g d'hydrure d'hydrure de lithium aluminium. Le mélange est agité pendant 45 min à 0°C. Après hydrolyse avec une solution aqueuse de sulfate de potassium, on extrait au diéthyléther jusqu'à épuisement de la phase aqueuse. Les phases organiques sont lavées avec une solution aqueuse d'acide chlorhydrique 3N, avec une solution aqueuse saturée d'hydrogénocarbonate de sodium, puis avec H2O et enfin avec une solution aqueuse saturée de chlorure de sodium. On sèche sur MgSO4 et on concentre à sec. On obtient 3,5 g de tert-butyl (3R)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate qui est utilisé tel quel par la suite.Was dissolved 7.4 g of tert -butyl (3 R) -3 - {[methoxy (methyl) amino] carbonyl} -3,4-dihydroisoquinoline-2 (1H) -carboxylate in 31 mL of diethyl ether under N 2. The reaction medium is placed at 0 ° C. and 0.98 g of lithium aluminum hydride hydride are slowly added. The mixture is stirred for 45 min at 0 ° C. After hydrolysis with an aqueous solution of potassium sulfate, the mixture is extracted with diethyl ether until the aqueous phase is exhausted. The organic phases are washed with an aqueous solution of 3N hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, then with H 2 O and finally with a saturated aqueous solution of sodium chloride. It is dried over MgSO 4 and concentrated to dryness. 3.5 g of tert -butyl (3 R) -3-formyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate, which was used as such subsequently.

6.3 : tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-methoxy-2-oxoethyl]amino} methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate6.3: tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2-methoxy-2-oxoethyl] amino} methyl) -3,4-dihydroisoquinoline-2 (1 H ) -carboxylate

On solubilise 3,5 g de tert-butyl (3R)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate dans 67 mL de dichlorométhane sous N2 en présence de 4,02 g d'ester méthylique de la D-4-chlorophenyl alanine et de 3,69 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. Après hydrolyse, on extrait dichlorométhane jusqu'à épuisement de la phase aqueuse. On sèche sur MgSO4 et on concentre à sec. Le brut est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de1 % à 3%. On obtient alors 6,1 g de tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-methoxy-2-oxoethyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.Is dissolved 3.5 g of tert -butyl (3 R) -3-formyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate in 67 mL of dichloromethane under N2 in the presence of 4.02 g of ester D-4-chlorophenylalanine methyl and 3.69 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. After hydrolysis, dichloromethane is extracted until the aqueous phase is exhausted. It is dried over MgSO 4 and concentrated to dryness. The crude is chromatographed on silica gel eluting with a gradient of methanol in dichloromethane ranging from 1% to 3%. Then 6.1 g of tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2-methoxy-2-oxoethyl] amino} methyl) -3,4 -dihydroisoquinoline-2 ( 1H ) -carboxylate.

6.4 : N-{[(3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-4-chloro-D-phenylalanine6.4: N - {[(3 R ) -2- ( tert -butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-3-yl] methyl} -4-chloro-D-phenylalanine

On solubilise 6,4 g de tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-methoxy-2-oxoethyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate dans 150 mL d'un mélange tétrahydrofurane/eau/MeoH (1/1/1) à 0°C et on ajoute 0,99 g d'hydroxyde de lithium hydrate. L'agitation est maintenue 3h à 0°C. on ajoute alors 0,5 g d'hydroxyde de lithium hydrate. Le milieu est maintenu à 0°C pendant 16h. On ajoute du sulfate, de potassium jusqu'à pH 7. Le précipité obtenu est essoré et rincé au diéthyléther. Après séchage sur P2O5, on obtient 7,2 g de N-{[(3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-4-chloro-D-phenylalanine.Is dissolved 6.4 g of tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2-methoxy-2-oxoethyl] amino} methyl) -3,4 dihydroisoquinoline-2 ( 1H ) -carboxylate in 150 mL of a mixture of tetrahydrofuran / water / MeOH (1/1/1) at 0 ° C and 0.99 g of lithium hydroxide hydrate. Stirring is maintained for 3 hours at 0 ° C. 0.5 g of lithium hydroxide hydrate is then added. The medium is maintained at 0 ° C. for 16 hours. Potassium sulphate is added to pH 7. The precipitate obtained is drained and rinsed with diethyl ether. After drying over P 2 O 5 is obtained 7.2 g of N- {[(3 R) -2- (tert -butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-3-yl] methyl} -4 chloro-D-phenylalanine.

6.5: tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino) carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate6.5: tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8-azabicyclo [3.2. 1] oct-8-yl) -2-oxoethyl] amino} methyl) -3,4-dihydroisoquinoline-2 ( 1H ) -carboxylate

On solubilise 0,2 g de composé endo N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N',N'-diethylurea obtenu à l'étape 1.3 dans 3,25 mL de dichlorométhane en présence de 0,35 g de N-{[(3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-4-chloro-D-phenylalanine obtenu à l'étape 6.5, de 0,088 g d'hydroxybenzotriazole, de 0,125 g de chlorhydrate de 1-(3-diméthylaminopropyl)-3-éthyl-carbodiimide et de 0,17 mL de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après évaporation à sec, le résidu est hydrolysé et extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 3%. On obtient 0,29 g de tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.0.2 g of endo N -8-azabicyclo [3.2.1] oct-3-yl- N -cyclohexyl- N ', N ' -diethylurea compound obtained in step 1.3 are solubilized in 3.25 ml of dichloromethane. 0.35 g of N - {[(3R) -2- ( tert -butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-3-yl] methyl} -4-chloro-D-phenylalanine, obtained at 0 ° C. step 6.5, 0.088 g of hydroxybenzotriazole, 0.125 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.17 ml of diisopropylethylamine. The mixture is stirred 16h at room temperature. After evaporation to dryness, the residue is hydrolysed and extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 3%. Was obtained 0.29 g of tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8 azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} methyl) -3,4-dihydroisoquinolin-2 ( 1H ) -carboxylate.

6.6 : N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea6.6: N - (8- {4-chloro-N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct- 3-yl) - N -cyclohexyl- N ', N ' -diethylurea

On place 0,29 g de tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino} methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate dans 1,1 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité 1h à température ambiante. Après hydrolyse avec une solution aqueuse de soude 1N, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. On sèche sur MgSO4 et on concentre à sec. Le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 98/2 de dichlorométhane et de méthanol. On obtient 0,12 g de N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea.Was placed 0.29 g of tert -butyl (3 R) -3 - ({[(1 R) -1- (4-chlorobenzyl) -2- (3- {cyclohexyl [(diethylamino) carbonyl] amino} -8 -azabicyclo [3.2.1] oct-8-yl) -2-oxoethyl] amino} methyl) -3,4-dihydroisoquinolin-2 ( 1H ) -carboxylate in 1.1 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 1 hour at room temperature. After hydrolysis with a 1N aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. It is dried over MgSO 4 and concentrated to dryness. The gross obtained is chromatographed on silica gel eluting with a 98/2 mixture of dichloromethane and methanol. To give 0.12 g of N - (8- {4-chloro- N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2 .1] oct-3-yl) - N- cyclohexyl- N ', N' -diethylurea.

6.7: Chlorhydrate de N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea6.7: N - (8- {4-chloro- N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) - N -cyclohexyl- N ', N ' -diethylurea

On dissout 0,12 g de N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea dans 5 mL de dichlorométhane et on ajoute 0,4 mL d'acide chlorhydrique 4N dans le dioxane. Après évaporation, on reprend le résidu dans le diéthyléther, on rince avec du diéthyléther et on essore le précipité obtenu. On obtient 0,12 g de chlorhydrate de N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo [3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea.
Point de fusion = 182°C, M+H+ = 634 , [α]D 20 =-10,2° (c=0,857 g/100 mL, DMSO).Was dissolved 0.12 g of N - (8- {4-chloro-N- [(3 R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2 .1] oct-3-yl) - N- cyclohexyl- N ', N' -diethylurea in 5 mL of dichloromethane and 0.4 mL of 4N hydrochloric acid in dioxane. After evaporation, the residue is taken up in diethyl ether, rinsed with diethyl ether and the precipitate obtained is filtered off with suction. To give 0.12 g of N - (8- {4-chloro- N - [(3R) -1,2,3,4-tetrahydroisoquinolin-3-ylmethyl] -D-phenylalanyl} -8-azabicyclo [3.2.1] oct-3-yl) -N- cyclohexyl- N ', N ' -diethylurea.
Melting point = 182 ° C, M + H + = 634, [α] D 20 = -10.2 ° (c = 0.857 g / 100 mL, DMSO).

Exemple 7 : N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea (composé n°23) Example 7 : N - {8- [4-chloro- N - (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N '-diethylurea (Compound No. 23) 7.1 : N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea7.1: N - {8- [4-chloro- N - (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N ', N '-diethylurea

On solubilise 0,24 g de N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea obtenu lors de l'étape 1.5 dans 3 mL de dichlorométhane, sous N2 en présence de 0,05 mL de 2-pyridine carboxaldehyde et de 0,22 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec et addition de 1 mL de méthanol et 4 g de résine DOWEX® 50X2, on agite pendant 1h30. Après filtration et lavage de la résine par du tétrahydrofurane et du méthanol, on relargue le composé attendu en ajoutant une solution 1 N d'ammoniaque dans le méthanol. Le méthanol est évaporé pour conduire à 0,054 g de N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea.0.24 g of N- [8- (4-chloro-D-phenylalanyl) -8-azabicyclo [3.2.1] oct-3-yl] -N- cyclohexyl- N ', N ' -diethylurea are solubilized from step 1.5 in 3 mL of dichloromethane, under N 2 in the presence of 0.05 mL of 2-pyridine carboxaldehyde and 0.22 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness and addition of 1 ml of methanol and 4 g of DOWEX ® 50X2, stirred for 1h30. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is recovered by adding a 1N solution of ammonia in methanol. The methanol is evaporated to yield 0.054 g of N- {8- [4-chloro- N- (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} - N -cyclohexyl- N ', N ' -diethylurea.

7.2: Chlorhydrate de N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea7.2: N - {8- [4-Chloro- N - (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3-yl} -N- cyclohexyl- N 'hydrochloride , N '-diethylurea

On place 0,054 g de dans 2 mL d'isopropanol et on ajoute 0,06 mL d'acide chlorhydrique 2N dans le déthyléther. Après évaporation, on reprend le résidu dans le diéthyléther , on rince avec du diéthyléther et on essore le précipité obtenu. On obtient 0,045 g de chlorhydrate de N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3'-yl}-N-cyclohexyl-N',N'-diethylurea.
Point de fusion = 119°C, M+H+ = 580.0.054 g of is placed in 2 ml of isopropanol and 0.06 ml of 2N hydrochloric acid in ethyl ether is added. After evaporation, the residue is taken up in the diethyl ether, rinsed with diethyl ether and the precipitate obtained. 0.045 g of N is obtained - {8- [4-chloro- N - (pyridin-2-ylmethyl) -D-phenylalanyl] -8-azabicyclo [3.2.1] oct-3'-yl} - N - cyclohexyl- N ' , N' -diethylurea.
Melting point = 119 ° C, M + H + = 580.

Le tableau qui suit illustre les structures chimiques et les propriétés physiques de quelques exemples de composés selon l'invention, à savoir des composés de formule (I bis), correspondant à des composés de formule (I) dans lesquels Ra = Ra' = R5 = H et R3 représente un atome de chlore situé en position para sur le noyau phényle auquel il est rattaché. Dans ce tableau :

  • dans la colonne « sel », « HCl» représente un composé sous forme de chlorhydrate,
  • « PF » représente le point de fusion mesuré pour le composé,
  • Me et Et représentent respectivement des groupes méthyle et éthyle.
Tableau
Figure imgb0023
 N° R1 R2 R4 Sel PF (°C) 1 cyclohexyl -CO-N(Et)2
Figure imgb0024
 HCl >210 2 cyclohexyl -CO-N(Et)2
Figure imgb0025
 HCl 162 3 cyclohexyl -CO-N(Et)2
Figure imgb0026
 HCl 208 4 cyclohexyl -CO-N(Et)2
Figure imgb0027
 HCl >210 5 cyclohexyl -CO-N(Et)2
Figure imgb0028
 HCl 155 6 cyclohexyl -CO-N(Et)2
Figure imgb0029
 HCl 171 7 cyclohexyl -CO-N(Et)2
Figure imgb0030
 HCl 166 8 cyclohexyl -CO-N(Et)2
Figure imgb0031
 HCl >200 9 cyclohexyl -CO-N(Et)2
Figure imgb0032
 HCl 192 10 cyclohexyl -CO-N(Et)2
Figure imgb0033
 HCl 159 11 cyclohexyl -CO-N(Et)2
Figure imgb0034
 HCl >200 12 cyclohexyl -CO-N(Et)2
Figure imgb0035
 CF3CO2H 90 13 cyclohexyl -CO-N(Et)2
Figure imgb0036
 HCl 14 cyclohexyl -CO-N(Et)2
Figure imgb0037
 HCl 152 15 cyclohexyl -CO-N(Et)2
Figure imgb0038
 HCl 162 16 cyclohexyl -CO-N(Et)2
Figure imgb0039
 HCl 220 17 cyclohexyl -CO-N(Et)2
Figure imgb0040
 HCl 176 18 cyclohexyl -CO-N(Et)2
Figure imgb0041
 HCl 105 19 cyclohexyl -CO-N(Et)2
Figure imgb0042
 HCl 215 20 cyclohexyl -CO-N(Et)2
Figure imgb0043
 HCl 132 21 cyclohexyl -CO-N(Et)2
Figure imgb0044
 HCl >200 22 cyclohexyl -CO-N(Et)2
Figure imgb0045
 HCl 182 23 cyclohexyl -CO-N(Et)2
Figure imgb0046
 HCl 119 24 cyclohexyl -CO-N(Et)2
Figure imgb0047
 HCl >200 25 cyclohexyl -CO-N(Et)2
Figure imgb0048
 HCl 26 cyclohexyl -CO-N(Et)2
Figure imgb0049
 HCl 27 cyclohexyl -CO-N(Et)2
Figure imgb0050
 HCl 170 28 cyclohexyl -CO-N(Et)2
Figure imgb0051
 HCl 158 The following table illustrates the chemical structures and the physical properties of some examples of compounds according to the invention, namely compounds of formula (Ia), corresponding to compounds of formula (I) in which R a = R a ' = R 5 = H and R 3 represents a chlorine atom located in the para position on the phenyl ring to which it is attached. In this table :
  • in the "salt" column, "HCl" represents a compound in the form of hydrochloride,
  • "PF" represents the melting point measured for the compound,
  • Me and Et respectively represent methyl and ethyl groups.
<B><u> Table </ u></b>
Figure imgb0023
 No. R 1 R 2 R 4 Salt PF (° C) 1 cyclohexyl -CO-N (and) 2
Figure imgb0024
 HCl > 210 2 cyclohexyl -CO-N (and) 2
Figure imgb0025
 HCl 162 3 cyclohexyl -CO-N (and) 2
Figure imgb0026
 HCl 208 4 cyclohexyl -CO-N (and) 2
Figure imgb0027
 HCl > 210 5 cyclohexyl -CO-N (and) 2
Figure imgb0028
 HCl 155 6 cyclohexyl -CO-N (and) 2
Figure imgb0029
 HCl 171 7 cyclohexyl -CO-N (and) 2
Figure imgb0030
 HCl 166 8 cyclohexyl -CO-N (and) 2
Figure imgb0031
 HCl > 200 9 cyclohexyl -CO-N (and) 2
Figure imgb0032
 HCl 192 10 cyclohexyl -CO-N (and) 2
Figure imgb0033
 HCl 159 11 cyclohexyl -CO-N (and) 2
Figure imgb0034
 HCl > 200 12 cyclohexyl -CO-N (and) 2
Figure imgb0035
 CF 3 CO 2 H 90 13 cyclohexyl -CO-N (and) 2
Figure imgb0036
 HCl 14 cyclohexyl -CO-N (and) 2
Figure imgb0037
 HCl 152 15 cyclohexyl -CO-N (and) 2
Figure imgb0038
 HCl 162 16 cyclohexyl -CO-N (and) 2
Figure imgb0039
 HCl 220 17 cyclohexyl -CO-N (and) 2
Figure imgb0040
 HCl 176 18 cyclohexyl -CO-N (and) 2
Figure imgb0041
 HCl 105 19 cyclohexyl -CO-N (and) 2
Figure imgb0042
 HCl 215 20 cyclohexyl -CO-N (and) 2
Figure imgb0043
 HCl 132 21 cyclohexyl -CO-N (and) 2
Figure imgb0044
 HCl > 200 22 cyclohexyl -CO-N (and) 2
Figure imgb0045
 HCl 182 23 cyclohexyl -CO-N (and) 2
Figure imgb0046
 HCl 119 24 cyclohexyl -CO-N (and) 2
Figure imgb0047
 HCl > 200 25 cyclohexyl -CO-N (and) 2
Figure imgb0048
 HCl 26 cyclohexyl -CO-N (and) 2
Figure imgb0049
 HCl 27 cyclohexyl -CO-N (and) 2
Figure imgb0050
 HCl 170 28 cyclohexyl -CO-N (and) 2
Figure imgb0051
 HCl 158

Les composés selon l'invention ont fait l'objet d'essais pharmacologiques permettant de déterminer leur effet agoniste des récepteurs aux mélanocortines, en particulier leur effet agoniste du récepteur MC3 et/ou MC4.The compounds according to the invention have been the subject of pharmacological tests for determining their agonist effect of melanocortin receptors, in particular their agonist effect of the MC3 and / or MC4 receptor.

Evaluation de l'affinité des composés de formule (I) selon l'invention envers les récepteurs MC3 et MC4Evaluation of the affinity of the compounds of formula (I) according to the invention for MC3 and MC4 receptors

Ce test d'affinité est réalisé par la mesure de la liaison du [125I]-[Nle4-D-Phe7]-α-MSH aux membranes cellulaires : le déplacement de ce radio-ligand est utilisé pour identifier des inhibiteurs de la liaison spécifique aux récepteurs recombinants mélanocortine.This affinity test is carried out by measuring the binding of [ 125 I] - [Nle 4 -D-Phe 7 ] -α-MSH to cell membranes: the displacement of this radioligand is used to identify inhibitors of specific binding to recombinant melanocortin receptors.

Pour ce test, on utilise des membranes préparées à partir des cellules CHO-K1 exprimant le récepteur humain MC4 à forte densité (Euroscreen) ou des membranes achetées (Perkin Elmer Life Sciences, Receptor Biology) des cellules HEK-293 exprimant des récepteurs hMC3. Les cellules CHO-K1 transfectées avec le gène du récepteur hMC4 (Euroscreen) sont ensemencées dans le milieu de culture DMEM/Nutrient Mix F12 contenant 10% sérum de veau (Biowhittaker), 1% pyruvate de sodium, 1% L-glutamine, 1% acides aminés non-essentiels, 0.4 mg/ml généticine (G418) et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau. Les cellules sont grattées à 80% de confluence et les culots de cellules sont congelés à -80°C.For this test, membranes prepared from CHO-K1 cells expressing the high density human MC4 receptor (Euroscreen) or purchased membranes (Perkin Elmer Life Sciences, Receptor Biology) of HEK-293 cells expressing hMC3 receptors are used. The CHO-K1 cells transfected with the hMC4 receptor gene (Euroscreen) are seeded in the DMEM / Nutrient Mix F12 culture medium containing 10% calf serum (Biowhittaker), 1% sodium pyruvate, 1% L-glutamine, 1 % non-essential amino acids, 0.4 mg / ml geneticin (G418) and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum. The cells are scraped at 80% confluency and the cell pellets are frozen at -80 ° C.

Un tube de cellules (environ 70 x 106 cellules) est décongelé sur glace et resuspendu dans 10 ml de tampon de binding [25 mM HEPES, pH 7.0, 1 mM MgCl2, 1.5 mM CaCl2, 100 mM NaCl, 1 mM 1,10-phenanthroline et 1 tablette de CompleteTR (inhibiteur de protéases de Roche) dans 50 ml de tampon] par polytronnage 20 s. La suspension est centrifugée 20 min à 19500 t/min à 4°C. Le surnageant est jeté et le culot est resuspendu dans 5 ml tampon de binding. Par un test de Bradford, on dose la quantité de protéines présentes dans l'échantillon et on ajuste la concentration à 3 µg/25 µl par dilution dans du tampon de binding. [125I]-[Nle4, D-Phe7]-α-MSH est dilué dans du tampon de binding + 0.2% BSA. Des billes SPA (wheatgerm agglutinine polyvinyltoluene, Amersham Pharmacia Biotech), sont hydratées dans le tampon de binding + 0.2% BSA et ensuite mélangées avec l'homogénat de cellules pour obtenir 3 µg de protéines cellulaires et 250 µg de billes dans 50 µl. Les produits à tester (dilués dans 10% DMSO), en quantité de 10 µl à une concentration de 10 fois la concentration finale, sont distribués dans une plaque blanche 96 puits à fond clair (CORNING 3604 Polystyrene Non-Binding Surface). Le binding non-spécifique est défini par NDP-αMSH à 10-7 M. Le binding total est mesuré par le nombre de coups par minute en présence du radio-ligand seul. La distribution de la suspension membranes-billes (50 µl/puits) est suivie par la distribution de la solution de [125I]-[Nle4, D-Phe7]-α-MSH, 40 µl/puits (100 pM concentration finale), pour un volume final de 100 µl/puits. Après 6 h. d'incubation à température ambiante, le comptage est fait dans un compteur de scintillation Microbeta TriLux. La valeur IC50 des composés correspond à la concentration qui déplace la liaison spécifique du radio-ligand de 50%.A tube of cells (approximately 70 x 10 6 cells) is thawed on ice and resuspended in 10 ml of binding buffer [25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 100 mM NaCl, 1 mM 1 , 10-phenanthroline and 1 tablet of Complete TR (Roche protease inhibitor) in 50 ml buffer] by 20 sec. The suspension is centrifuged for 20 minutes at 19500 rpm at 4 ° C. The supernatant is discarded and the pellet is resuspended in 5 ml of binding buffer. Using a Bradford test, the amount of protein present in the sample is measured and the concentration is adjusted to 3 μg / 25 μl by dilution in binding buffer. [ 125 I] - [Nle 4 , D-Phe 7 ] -α-MSH is diluted in binding buffer + 0.2% BSA. SPA beads (wheatgerm agglutinin polyvinyltoluene, Amersham Pharmacia Biotech) are hydrated in the binding buffer + 0.2% BSA and then mixed with the cell homogenate to obtain 3 μg of cellular proteins and 250 μg of beads in 50 μl. The products to be tested (diluted in 10% DMSO), in an amount of 10 μl at a concentration of 10 times the final concentration, are distributed in a white-colored 96-well plate (CORNING 3604 Polystyrene Non-Binding Surface). The nonspecific binding is defined by NDP-αMSH at 10 -7 M. The total binding is measured by the number of counts per minute in the presence of the radioligand alone. The distribution of the membrane-bead suspension (50 μl / well) is followed by the distribution of the solution of [ 125 I] - [Nle 4 , D-Phe 7 ] -α-MSH, 40 μl / well (100 μM final concentration), for a final volume of 100 μl / well. After 6 pm incubation at room temperature, counting is done in a Microbeta TriLux scintillation counter. The IC 50 value of the compounds corresponds to the concentration which displaces the specific binding of the radioligand by 50%.

On détermine ainsi que les composés selon l'invention présentent une affinité .. pour les récepteurs MC3 et/ou MC4. Leurs IC50 envers les récepteurs MC3 et MC4 sont inférieures à 10 µM, pour la plupart comprises entre 1 nM et 1 µM. A titre d'exemple, le composé n° 3 du tableau présente une IC50 de 280 nM envers le récepteur MC4.It is thus determined that the compounds according to the invention have an affinity for the MC3 and / or MC4 receptors. Their IC 50 towards the MC3 and MC4 receptors are less than 10 μM, mostly between 1 nM and 1 μM. By way of example, Compound No. 3 of the table has an IC 50 of 280 nM towards the MC4 receptor.

Evaluation de l'activité agoniste des composés de formule (I) selon l'invention envers les récepteurs MC3 et MC4Evaluation of the agonist activity of the compounds of formula (I) according to the invention towards MC3 and MC4 receptors

Un test fonctionnel est utilisé pour discriminer l'activité agoniste de l'activité antagoniste. Pour cela, on dose la formation d'adénosine - mono-phosphate cyclique (AMPc) générée par l'activation du récepteur-MC3 ou du récepteur MC4.A functional test is used to discriminate the agonist activity of the antagonist activity. For this purpose, the adenosine-cyclic mono-phosphate (cAMP) formation generated by the activation of the MC3 receptor or the MC4 receptor is measured.

Les cellules CHO-K1, exprimant le récepteur humain MC4 à une densité modérée (Euroscreen), sont ensemencées dans le milieu de culture DMEM / Nutrient Mix F12 (Gibco/BRI) contenant 10% de sérum de veau, 0.5% pyruvate de sodium, 1% L-glutamine, 1 % acides aminés non-essentiels, 200 mg/l hygromycine B et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau (Biowhittaker) et l'hygromycine B (Sigma).The CHO-K1 cells, expressing the human MC4 receptor at a moderate density (Euroscreen), are seeded in the DMEM / Nutrient Mix F12 culture medium (Gibco / BRI) containing 10% calf serum, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-essential amino acids, 200 mg / l hygromycin B and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum (Biowhittaker) and hygromycin B (Sigma) .

Les cellules CHO(dhfr-) exprimant le récepteur humain MC3 sont ensemencées dans le milieu de culture MEM Eagle (Sigma) contenant 10% de sérum de veau dialysé, 1% L-glutamine, 1% pyruvate de sodium, 20mg/500 ml L-proline, 0.3 mg/ml Geneticin et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau dialysé (Cambrex) et la L-proline (Sigma).The CHO cells (dhfr-) expressing the human MC3 receptor are seeded in the Eagle (Sigma) MEM culture medium containing 10% dialyzed calf serum, 1% L-glutamine, 1% sodium pyruvate, 20 mg / 500 ml. -proline, 0.3 mg / ml Geneticin and 0.5% PenStrep, these products being supplied by Gibco / BRI, except dialyzed calf serum (Cambrex) and L-proline (Sigma).

Les composés à tester (dilués dans 10% DMSO), en quantité de 10 µl à une concentration de 10 fois la concentration finale, sont ajoutés aux plaques de cellules (volume final = 100 µl/puits). Après 1 heure d'incubation (37°C, 5% CO2), la quantité du AMPc est dosée utilisant des kits du TROPIX (Appelera) selon la documentation du fournisseur. L'activité intrinsèque des composés est calculée en comparant la stimulation d'AMPc par ces composés à la stimulation induite par 30 nM de NDPαMSH (100% maximum). La valeur EC50 des composés correspond à la concentration qui produit 50% de la stimulation maximale obtenue avec ce composé.The compounds to be tested (diluted in 10% DMSO), in an amount of 10 μl at a concentration of 10 times the final concentration, are added to the cell plates (final volume = 100 μl / well). After 1 hour of incubation (37 ° C., 5% CO 2 ), the amount of cAMP is assayed using TROPIX kits (Appelera) according to the supplier's documentation. The intrinsic activity of the compounds is calculated by comparing cAMP stimulation by these compounds to stimulation induced by 30 nM NDPαMSH (100% maximum). The EC 50 value of the compounds corresponds to the concentration which produces 50% of the maximal stimulation obtained with this compound.

On détermine ainsi que les composés selon l'invention sont des agonistes des récepteurs MC3 et/ou MC4. Ils présentent des EC50 envers les récepteurs MC3 et MC4 inférieures à 10 µM, pour la plupart comprises entre 1 nM et 1 µM. A titre d'exemples, le composé n° 3 du tableau présentent un EC50 de 330 nM envers le récepteur MC3, et de 28 nM envers le récepteur MC4.It is thus determined that the compounds according to the invention are agonists of the MC3 and / or MC4 receptors. They have EC 50 towards MC3 and MC4 receptors less than 10 μM, mostly between 1 nM and 1 μM. By way of example, compound No. 3 of the table shows an EC 50 of 330 nM towards the MC3 receptor, and 28 nM towards the MC4 receptor.

Les composés selon l'invention présentant une activité agoniste des récepteurs aux mélanocortines, ils peuvent donc être utilisés pour la préparation de médicaments. Ainsi, selon un autre de ses aspects, l'invention a pour objet des médicaments qui comprennent un composé de formule (I), ou un sel d'addition de ce dernier à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvat du composé de formule (I).The compounds according to the invention having a melanocortin receptor agonist activity, they can therefore be used for the preparation of medicaments. Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of compound of formula (I).

Ces médicaments trouvent leur emploi en thérapeutique, dans les pathologies dans lesquelles les récepteurs aux mélanocortines, en particulier les récepteurs MC3 et/ou MC4, sont impliqués: il s'agit notamment du traitement et de la prévention de l'obésité, du diabète et des dysfonctions sexuelles pouvant affecter les deux sexes, telles que les dysfonctionnements érectiles, les maladies cardiovasculaires telles que les infarctus du myocarde ou l'hypertension ainsi que dans des applications antiinflammatoires ou dans le traitement de dépendance alcoolique.These drugs find their therapeutic use, in the pathologies in which the melanocortin receptors, in particular the MC3 and / or MC4 receptors, are involved: these include the treatment and prevention of obesity, diabetes and sexual dysfunction that can affect both sexes, such as erectile dysfunction, cardiovascular diseases such as myocardial infarction or hypertension, as well as anti-inflammatory or alcohol dependence treatment.

Selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques comprenant, en tant que principe actif, un composé selon l'invention: Ces compositions pharmaceutiques contiennent une dose efficace d'au moins un composé selon l'invention, ou un sel pharmaceutiquement acceptable, un hydrate ou solvat dudit composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention: These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a salt pharmaceutically acceptable, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.

Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus de l'Homme du métier.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra-veineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, le principe actif de formule (I) ci-dessus, ou son sel, solvat ou hydrate éventuel, peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des troubles ou des maladies ci-dessus.In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, on peut utiliser les composés selon l'invention dans des crèmes, gels, pommades ou lotions.Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

Une forme d'administration préférée est la voie orale.A preferred form of administration is the oral route.

A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants : Composé selon l'invention 50,0 mg Mannitol 223,75 mg Croscaramellose sodique 6,0 mg Amidon de maïs 15,0 mg Hydroxypropyl-méthylcellulose 2,25 mg Stéarate de magnésium 3,0 mg By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

Il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient.There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

Claims (15)

  1. Compound corresponding to formula (I):
    Figure imgb0059
     in which:
    Ra and Ra' , which may be identical to or different from one another, represent a hydrogen atom, or an alkyl or cycloalkyl group,
    R1 represents a hydrogen atom, or an alkyl, cycloalkyl, heterocycloalkyl or aryl group,
    R2 represents a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which:
    • x = 0, 1, 2, 3 or 4,
    • y = 0 or 1,
    • Y represents a hydrogen atom, or a hydroxyl, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl or -NR11R12 group, Y being different from a hydrogen atom when x = y = 0,
    • R11 and R12 which may be identical to or different from one another, represent a hydrogen atom, or an alkyl, cycloalkyl, alkoxy or -NR13R14 group, or else R11 and R12 form, together with the nitrogen atom to which they are attached, a mono- or bicyclic structure containing from 4 to 10 ring members and optionally comprising 1 to 3 additional hetero atoms and/or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any of the positions with 1 to 3 groups chosen from halogen atoms, and hydroxyl, alkyl, cycloalkyl and alkoxy groups,
    • R13 and R14, which may be identical to or different from one another, represent a hydrogen atom, or an alkyl, cycloalkyl or alkoxy group, or else R13 and R14 form, together with a nitrogen atom to which they are attached, a mono- or bicyclic structure as defined above,
    R3 represents 1 to 3 groups, which may be identical to or different from one another, located in any positions of the ring to which they are attached and chosen from halogen atoms, and alkyl, cycloalkyl, -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR groups,
    R5 represents a hydrogen atom or an alkyl,
    R4 is chosen from:
    (1) a group of formula (a), (b) or (c) optionally substituted with an oxo group:
    Figure imgb0060
     in which each of the rings of formulae (a), (b) and (c) may be substituted, in any positions, with 1 to 4 groups R7, which may be identical to or different from one another, and in which:
    a = 0, 1, 2 or 3,
    p = 0, 1, 2 or 3,
    m = 0, 1 or 2,
    X represents an oxygen or sulphur atom, or a ring member -C (R6) (R7) - or -N(R10)-,
    R6 is chosen from:
    • a hydrogen atom, a halogen atom,
    • a group -(CH2)x-OR8, - (CH2)x-COOR8, - (CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or - (CH2)x-NR8-COR9, in which x = 0, 1, 2, 3 or 4,
    • an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR8R9 or -C(=NH) -NR8R9 group,
    • a fused or nonfused cycloalkyl or heterocycloalkyl group located in the spiro position on the ring of formula (a) to which it is attached,
    . a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
    R7 is chosen from hydrogen and halogen atoms, and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -0-heteroaryl, -0-alkylaryl, -O-alkylheteroaryl, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR groups,
    R8 and R9 are chosen, independently of one another, from a hydrogen atom, and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocycloalkyl, -SO2-aryl, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-alkylheteroaryl, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' and - (CH2)x-OR groups, where x = 0, 1, 2, 3 or 4;
    or else R8 and R9 together form a cycloalkyl or a heterocycloalkyl;
    R10 is chosen from:
    • a hydrogen atom,
    • a group - (CH2) X-OR8, - (CH2)x-COOR8, -(CH2)x-NR8R9, - ( CH2)x-CO-NR8R9, - (CH2)x-NR8-COR9 or - (CH2)x-COR8, in which x = 0, 1, 2, 3 or 4,
    • a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
    • ain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR8R9, -C (=NH) -NR8R9, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocycloalkyl, -SO2-aryl, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-alkylheteroaryl or -SO2-NR8R9 group,
    • or else R10 forms, with the nitrogen atom to which it is attached and a carbon atom located in any position of the cyclic structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members,
    R and R' represent, independently of one another, a hydrogen atom, or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
    the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted with one or more groups chosen from the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN and -COOR, OCOR, COR, OCONRR', NRCOOR',
    (2) a group of formula -A-R18, -A-CH=N-R19, -A-N (R20) -A' -R19, -A-CO-N (R20) -A' -R19, -A-CH (NH2) -R19 or -A-N (R20) -COO-A', in which A and A' represent a linear or branched alkyl group, R18 represents a halogen atom, or an -NH2, hydroxyl or phenyl group, R19 represents a hydrogen atom, or a hydroxyl, phenyl, benzyl or heteroaryl group, and R20 represents a hydrogen atom or a benzyl group,
    (3) a group of formula (d):
    Figure imgb0061
     optionally substituted, in any positions, with 1 to 4 groups R7, which may be identical to or different from one another, as defined above, and in which r is equal to 1, 2 or 3, s is equal to 0 or 1, and one of U, V or W represents a nitrogen atom, the others among U, V and W representing methylene ring members, or
    (4) a -(CH2)r-heteroaryl group, where r is equal to 1, 2 or 3,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  2. Compound of formula (I) according to Claim 1, characterized in that R1 represents a cycloalkyl group,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  3. Compound of formula (I) according to Claim 1 or Claim 2, characterized in that R2 is chosen from the following groups: -CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-aryl, -CO-heteroaryl, -CO- (CH2)x-NR16R17, - (CH2)x-NR16R17' - (CH2)x-OH, - (CH2)x-aryl, -(CH2)x-heteroaryl, -(CH2)x'-CO-R15 and - (CH2)x' -CO-NR16R17, in which:
    • x = 0, 1, 2, 3 or 4 and x' = 1, 2, 3 or 4,
    • R15 represents a hydrogen atom, or an alkyl, cycloalkyl or alkoxy group, and
    R16 and R17, which may be identical to or different from one another, represent a hydrogen atom, or an alkyl, cycloalkyl or alkoxy group, or else R16 and R17 form, together with the nitrogen atom to which they are attached, a mono- or bicyclic structure containing from 4 to 10 ring members and optionally comprising 1 to 3 additional hetero atoms and/or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any positions with 1 to 3 groups chosen from halogen atoms, and hydroxyl, alkyl, cycloalkyl and alkoxy groups,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  4. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that R2 represents a group -CO-NR16R17, where R16 and R17 represent alkyl or alkoxy groups,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  5. Compound of formula (I) according to any one of Claims 1 to 4, characterized in that R3 represents 1 to 3 groups, which may be identical to or different from one another, chosen from halogen atoms,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  6. Compound of formula (I) according to any one of Claims 1 to 5, characterized in that R4 is chosen from:
    (1) a group of formula (a-5), (a-6) or (b-2) below:
    Figure imgb0062
     in which each of the rings of formulae (a-5), (a-6) and (b-2) can be substituted, in any positions, with 1 to 4 groups R7, which may be identical to or different from one another, as defined in Claim 1, and in which a' = 0 or 1, p' = 0 or 1, and R6, R7 and R10 are as defined in Claim 1,
    (2) a group of formula -A-R18 or -A-CH=N-R19, where A, R18 and R19 are as defined in Claim 1,
    (3) a group of formula (d-1), where r = 1, 2 or 3:
    Figure imgb0063
    (4) a group -(CH2)r-furyl or -(CH2)r-pyridinyl, where r is equal to 1, 2 or 3,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  7. Compound of formula (I) according to any one of Claims 1 to 6, characterized in that R5 represents a hydrogen atom,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  8. Compound of formula (I) according to any one of Claims 1 to 7, characterized in that Ra = Ra' = H,
    in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate.
  9. Method for preparing a compound of formula (I) according to any one of Claims 1 to 8, characterized in that a reductive amination of a compound of formula (V):
    Figure imgb0064
     is carried out in the presence of a derivative of the group R4 of ketone type, R1, R2, R3, R4, R5, Ra and Ra' being as defined in any one of Claims 1 to 8.
  10. Compounds of formulae (IV) and (V), in which R1, R2, R3, R5, Ra and Ra' are as defined in any one of Claims 1, 2, 3, 4, 5, 7 and 8, and Pg represents a protective group:
    Figure imgb0065
  11. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 8, or an addition salt of this compound with a pharmaceutically acceptable acid, or else a hydrate or a solvate of the compound of formula (I).
  12. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and also at least one pharmaceutically acceptable excipient.
  13. Use of a compound of formula (I) according to any one of Claims 1 to 8, in the manufacture of a medicament for use in the treatment and in the prevention of obesity, diabetes and sexual dysfunctions that can affect both sexes, in the treatment of cardiovascular diseases, and also in antiinflammatory uses or in the treatment of alcohol dependency.
  14. Use according to Claim 13, characterized in that said sexual dysfunctions consist of erectile dysfunctions.
  15. Compounds of formula (I) having the following names:
    1: N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    2: N-[8-(4-chloro-N-piperidin-3-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    3: N-{8-[N-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    4: N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    5: N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    6: N-{8-[4-chloro-N-(piperidin-4-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    7: N-{8-[4-chloro-N-(piperidin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    8: N-{8-[4-chloro-N-(tetrahydro-3-thienyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    9: N-[8-(N-1-azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    10: N-[8-(N-azepan-4-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    11: N- [8-(4-chloro-N-{[(2S, 4R)-4-hydroxy-pyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    12 : N-[8-(4-chloro-N-{[(2R, 4R)-4-hydroxy-pyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    13: N-[8-(4-chloro-N-{[(2R, 4S)-4-hydroxy-pyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    14: N-{8-[4-chloro-N-(1-phenylpiperidin-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    15: N-(8-{N-[(1-benzylpyrrolidin-3-yl)-methyl]-4-chloro-D-phenylalanyl}-8-azabicyclo-[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    16: N-[8-(4-chloro-N-pyrrolidin-3-yl-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    17 : N-(8-{4-chloro-N-[4-(4-hydroxyphenyl)-cyclohexyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    18: N-{8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N', N'-diethylurea
    19: N-{8-[N-(3-aminopropyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    20: N-(8-{4-chloro-N-[(2E)-2-(hydroxyimino)-1-methylethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    21: N-{8-[4-chloro-N-(2-fluoro-1-methylethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    22: N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetra-hydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    23: N-{8-[4-chloro-N-(pyridin-2-ylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    24: N-{8-[4-chloro-N-(2-furylmethyl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N',N'-diethylurea
    25: N-(8-{4-chloro-N-[(2R)-pyrrolidin-2-yl-methyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    26: N-(8-{4-chloro-N-[(2S)-pyrrolidin-2-yl-methyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
    27: N-[8-(iN-azetidin-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N',N'-diethylurea
    28: N-(8-{N-[(1-benzylpyrrolidin-3-yl)-methyl]-4-chloro-D-phenylalanyl}-8-azabicyclo[3.2.1]-oct-3-yl)-N-cyclohexyl-N',N'-diethylurea
EP05790816A 2004-07-29 2005-07-20 Amino-tropane derivatives, preparation thereof and therapeutic use thereof Active EP1773829B1 (en)

Priority Applications (3)

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PL05790816T PL1773829T3 (en) 2004-07-29 2005-07-20 Amino-tropane derivatives, preparation thereof and therapeutic use thereof
SI200530620T SI1773829T1 (en) 2004-07-29 2005-07-20 Amino-tropane derivatives, preparation thereof and therapeutic use thereof
CY20091100292T CY1108878T1 (en) 2004-07-29 2009-03-17 AMINO-TROPANIS PRODUCTS, THEIR PREPARATION AND THEIR APPLICATIONS IN THERAPEUTICS

Applications Claiming Priority (2)

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FR0408372A FR2873693B1 (en) 2004-07-29 2004-07-29 AMINO-TROPANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
PCT/FR2005/001856 WO2006021657A1 (en) 2004-07-29 2005-07-20 Amino-tropane derivatives, preparation thereof and therapeutic use thereof

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EP1773829B1 true EP1773829B1 (en) 2008-12-17

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KR (1) KR20070047803A (en)
CN (1) CN101010320B (en)
AR (1) AR050019A1 (en)
AT (1) ATE417846T1 (en)
AU (1) AU2005276355B2 (en)
BR (1) BRPI0513923A (en)
CA (1) CA2574517A1 (en)
CY (1) CY1108878T1 (en)
DE (1) DE602005011818D1 (en)
DK (1) DK1773829T3 (en)
ES (1) ES2319918T3 (en)
FR (1) FR2873693B1 (en)
HR (1) HRP20090160T1 (en)
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PE (1) PE20060575A1 (en)
PL (1) PL1773829T3 (en)
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RU (1) RU2389727C2 (en)
SI (1) SI1773829T1 (en)
TW (1) TW200617005A (en)
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FR2873691B1 (en) * 2004-07-29 2006-10-06 Sanofi Synthelabo AMINO-PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2873690B1 (en) * 2004-07-29 2006-10-13 Sanofi Synthelabo OXOPIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2007028770A1 (en) * 2005-09-05 2007-03-15 Neurosearch A/S Monoamine neurotransmitter re-uptake inhibitors for neuroprotection in patients suffering from an advanced stage of a mental disease
ES2391625T3 (en) * 2007-06-07 2012-11-28 Novartis Ag Stabilized amorphous forms of imatinib mestilate
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
PL2074120T3 (en) * 2007-10-25 2010-08-31 Exelixis Inc Tropane compounds
US8153653B2 (en) * 2010-06-22 2012-04-10 Hoffmann-La Roche Inc. Amido-tropane derivatives
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
US8895547B2 (en) 2011-03-08 2014-11-25 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
EP2683698B1 (en) 2011-03-08 2017-10-04 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof

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US5968929A (en) * 1996-10-30 1999-10-19 Schering Corporation Piperazino derivatives as neurokinin antagonists
IL129660A0 (en) * 1996-10-30 2000-02-29 Schering Corp Piperazino derivatives as neurokinin antagonists
US7169777B2 (en) * 2001-01-23 2007-01-30 Eli Lilly And Company Melanocortin receptor agonists
CA2453609C (en) * 2001-07-18 2010-05-04 Merck & Co., Inc. Bridged piperidine derivatives as melanocortin receptor agonists
WO2003061660A1 (en) * 2002-01-23 2003-07-31 Eli Lilly And Company Melanocortin receptor agonists

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IL180797A0 (en) 2007-06-03
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IL180797A (en) 2011-02-28
ES2319918T3 (en) 2009-05-14
RU2389727C2 (en) 2010-05-20
UY29040A1 (en) 2006-02-24
FR2873693A1 (en) 2006-02-03
AR050019A1 (en) 2006-09-20
DK1773829T3 (en) 2009-04-20
FR2873693B1 (en) 2006-09-15
DE602005011818D1 (en) 2009-01-29
WO2006021657A1 (en) 2006-03-02
JP2008508242A (en) 2008-03-21
PL1773829T3 (en) 2009-06-30
CN101010320A (en) 2007-08-01
US7569582B2 (en) 2009-08-04
MX2007001023A (en) 2007-04-16
HRP20090160T1 (en) 2009-05-31
PT1773829E (en) 2009-03-26
US20070191361A1 (en) 2007-08-16
CA2574517A1 (en) 2006-03-02
TW200617005A (en) 2006-06-01
CY1108878T1 (en) 2014-07-02
SI1773829T1 (en) 2009-06-30
KR20070047803A (en) 2007-05-07
AU2005276355B2 (en) 2011-08-25
AU2005276355A1 (en) 2006-03-02
RU2007107372A (en) 2008-09-10
ATE417846T1 (en) 2009-01-15
EP1773829A1 (en) 2007-04-18
CN101010320B (en) 2011-11-16

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